Pyrrolidine derivatives as prostaglandin modulators

ABSTRACT

Substituted pyrrolidine compounds are provided, and methods of treatment and pharmaceutical composition that utilize or comprise one or more such compounds. Compounds of the invention are useful for a variety of therapies, including treating or preventing preterm labor, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteoporosis and other destructive bone disease or disorder, and other diseases and disorders associated with the prostaglandin family of compounds. In a preferred aspect, a substituted pyrrolidine compound is administered to a subject in coordination with a phosphodiesterase inhibitor compound.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention provides substituted pyrrolidine compounds, and methodsof treatment and pharmaceutical compositions that utilize or compriseone or more such compounds. Compounds of the invention are useful for avariety of therapies, including preterm labor, dysmenorrhea, asthma,hypertension, infertility or fertility disorder, undesired bloodclotting, preeclampsia or eclampsia, an eosinophil disorder, sexualdysfunction, osteoporosis and other destructive bone disease ordisorder, and other diseases and disorders associated with theprostaglandin and receptors thereof.

2. Background

Certain prostanoid receptors and modulators of those receptors have beenreported. See generally Eicosanoids: From Biotechnology to TherapeuticApplications (Plenum Press, New York); Journal of Lipid Mediators andCell Signalling 14:83-87 (1996); The British Journal of Pharmacology,112:735-740 (1994); PCT applications WO 96/06822, WO 97/00863, WO97/00864, and WO 96/03380; EP 752421; U.S. Pat. Nos. 6,211,197 4,211,876and 3,873,566; and Bennett et al. J. Med. Chem., 19(5): 715-717 (1976).

Certain prostaglandin ligands and analogs have been reported to providebiological activity associated with prostaglandin. See, for instance,U.S. Pat. Nos. 6,288,120; 6,211,197; 4,090,019; and 4,033,989. See alsoU.S. Pat. No. 4,003,911. E-type prostaglandin reported to be mediatedthrough interaction with the prostaglandin E receptor(s). Four subtypesof the prostaglandin EP receptor have been identified: EP1, EP2, EP3,and EP4. See U.S. Pat. Nos. 5,605,814 and 5,759,789. See U.S. Pat. No.5,605,814.

It would be desirable to have new compounds and methods for treatment ofdiseases and disorders associated with the prostaglandin family ofcompounds.

SUMMARY OF THE INVENTION

We have now found substituted pyrrolidine compounds that are useful fora variety of therapies, including alleviating, preventing and/ortreating preterm labor, dysmenorrhea, asthma, hypertension, sexualdysfunction, osteoporosis and other destructive bone disease ordisorder, inflammation, and other diseases and disorders associated withthe prostaglandin.

Preferred compounds of the invention are substituted at least two otherpyrrolidine ring positions in addition to N-substitution, particularlyat the 2 and 3 ring positions in addition to N-substitution.

Generally preferred for use in accordance with the invention aresubstituted pyrrolidine compounds of the following Formula I:

wherein Y, R and each R′ are each independently hydrogen or anon-hydrogen substituent, preferably where one or both of R and R′ arenon-hydrogen substituents such as optionally substituted alkylpreferably having 1 to about 20 carbons; optionally substituted alkenylpreferably having from 2 to about 20 carbons; optionally substitutedalkynyl preferably having from 2 to about 20 carbons; optionallysubstituted heteroalkyl preferably having from 1 to about 20 carbons;optionally substituted heteroalkenyl preferably having from 2 to about20 carbons; optionally substituted heteroalkynyl preferably having from2 to about 20 carbons; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroalicyclic;optionally substituted heteroaryl; optionally substitutedheteroarylalkyl; or optionally substituted heteroalicyclicalkyl;

G is oxo (═O), halogen particularly Cl or F, optionally substitutedalkyl particularly fluoroalkyl, optionally substituted alkoxy, hydroxy,carboxylate, or optionally substituted alkylcarboxylate ester;

p is an integer of from zero (i.e. no R′ groups) to 4; andpharmaceutically acceptable salts thereof.

For many applications, more preferred are N-substituted pyrrolidinecompounds of the following Formula II:

wherein R, R′, G and p are the same as defined in Formula I above;

Y is (CR²R³)_(q) which may include 0 or 1 carbon-carbon double bond ortriple bond, q is from 1 to 6 and R² and R³ are each independentlyselected at each occurrence from the group consisting of hydrogen,hydroxy, halogen, optionally substituted alkyl preferably having from 1to about 12 carbon atoms, optionally substituted alkenyl preferablyhaving from 2 to about 12 carbon atoms, optionally substituted alkynylpreferably having from 2 to about 12 carbon atoms, optionallysubstituted heteroalkyl preferably having from 1 to about 12 carbonatoms particularly optionally substituted alkoxy preferably having from1 to about 12 carbon atoms, optionally substituted heteroalkenylpreferably having from 2 to about 12 carbon atoms, optionallysubstituted heteroalkynyl preferably having from 2 to about 12 carbonatoms, or R² and R³ together may be a single oxygen to provide acarbonyl (>C═O) group; and

U and U′ axe each independently selected from hydrogen, hydroxy,optionally substituted alkyl preferably having from 1 to about 12 carbonatoms, optionally substituted cycloalkyl preferably having 3 to about 8carbon ring atoms, optionally substituted alkenyl preferably having from2 to about 12 carbon atoms, optionally substituted alkynyl preferablyhaving from 2 to about 12 carbon atoms, optionally substitutedheteroalkyl preferably having from 1 to about 12 carbon atomsparticularly optionally substituted alkoxy preferably having from 1 toabout 12 carbon atoms, optionally substituted heteroalkenyl preferablyhaving from 2 to about 12 carbon atoms, optionally substitutedheteroalkynyl preferably having from 2 to about 12 carbon atoms; andpharmaceutically acceptable salts thereof.

Also preferred are compounds of the following Formula III:

wherein G, R′ and p are the same as defined in Formula I; and Y, U, U′and q are the same as defined in Formula II;

A is O, S, (CR²R³)_(q), where q′ is an integer of from 1 to 6;

B is (CR²R³)_(n), or absent; or

A and B taken in combination form an optionally substituted 1,2-vinylenegroup or an ethynyl group;

V is (CR²R³)_(m), optionally substituted divalent aryl, or optionallysubstituted divalent heteroaryl;

L is C(O)Z;

Z is hydroxy, optionally substituted alkyl preferably having 1 to about12 carbon atoms, optionally substituted alkenyl preferably having 2 toabout 12 carbon atoms, optionally substituted alkynyl preferably having2 to about 12 carbon atoms, optionally substituted heteroalkylpreferably having from 1 to about 12 carbon atoms particularlyoptionally substituted alkoxy preferably having from 1 to about 12carbon atoms, optionally substituted heteroalkenyl preferably havingfrom 2 to about 12 carbon atoms, optionally substituted heteroalkynylpreferably having from 2 to about 12 carbon atoms, amino, NR⁴R⁵,optionally substituted cycloalkyl preferably having 3 to 8 ring carbonatoms, optionally substituted heterocycloalkyl preferably having 3 to 8ring atoms with at least one N, O or S ring atoms, optionallysubstituted carbocyclic aryl, optionally substituted heteroaryl,optionally substituted arylalkyl preferably aryl C₁₋₄alkyl, oroptionally substituted heteroarylalkyl preferably heteroaryl C₁₋₄alkyl;

n is an integer selected from 0-3;

m is an integer selected from 1-6;

R², R³ and q are the same as defined in Formula II;

R⁴ and R⁵ are independently selected at each occurrence from the groupconsisting of hydrogen optionally substituted alkyl preferably having 1to about 12 carbon atoms, optionally substituted cycloalkyl preferablyhaving 3 to about 8 ring carbon atoms, optionally substitutedheterocycloalkyl preferably having 3 to about 8 ring atoms at least oneof which is N, O or S, optionally substituted alkenyl preferably having2 to about 12 carbon atoms, optionally substituted alkynyl preferablyhaving 2 to about 12 carbon atoms, optionally substituted heteroalkylpreferably having from 1 to about 12 carbon atoms particularlyoptionally substituted alkoxy preferably having from 1 to about 12carbon atoms, optionally substituted heteroalkenyl preferably havingfrom 2 to about 12 carbon atoms, optionally substituted heteroalkynylpreferably having from 2 to about 12 carbon atoms, optionallysubstituted carbocyclic aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, and optionally substitutedheteroarylalkyl,

or R⁴ and R⁵ taken in combination is an optionally substitutedheterocycloalkyl preferably having 3 to about 8 ring atoms at least oneof which is N, O or S; and pharmaceutically acceptable salts thereof.

Preferred compounds of the invention also include those of the followingFormula IV:

wherein

A is O, S, CR²R³;

B is (CR²R³)_(n), or absent; or

A and B taken in combination form an optionally substituted 1,2-vinylenegroup or an ethynyl group;

V is (CR²R³)_(m), optionally substituted divalent aryl, or optionallysubstituted divalent heteroaryl;

L is C(O)Z;

G is oxo (═O), halo particularly Cl or F, optionally substituted alkyl,optionally substituted alkoxy, optionally substituted fluoroalkyl,hydroxy, carboxylate, or optionally substituted alkylcarboxylate ester;

Q is (CR²R³)_(q) which may include 0 or 1 C═C double bonds;

U is an optionally substituted alkyl group;

Z is hydroxy, optionally substituted alkyl preferably having 1 to about12 carbon atoms, optionally substituted alkenyl preferably having 2 toabout 12 carbon atoms, optionally substituted alkynyl preferably having2 to about 12 carbon atoms, optionally substituted heteroalkyl alkylpreferably having from 1 to about 12 carbon atoms particularlyoptionally substituted alkoxy preferably having from 1 to about 12carbon atoms, optionally substituted heteroalkenyl preferably havingfrom 2 to about 12 carbon atoms, optionally substituted heteroalkynylpreferably having from 2 to about 12 carbon atoms, amino, NR⁴R⁵,optionally substituted cycloalkyl preferably having 3 to 8 carbon ringatoms, optionally substituted heterocycloalkyl preferably having 3 to 8ring atoms with at least one N, O or S ring atom, optionally substitutedcarbocyclic aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl preferably aryl C₁₋₄alkyl, or optionallysubstituted heteroarylalkyl preferably heteroaryl C₁₋₄alkyl;

n is an integer selected from 0-3;

m is an integer selected from 1-6;

q is an integer selected from 0-5;

R² and R³ are independently selected at each occurrence from the groupconsisting of hydrogen, hydroxy, halogen, optionally substituted alkylpreferably having 1 to about 12 carbon atoms, optionally substitutedalkenyl preferably having 2 to about 12 carbon atoms, optionallysubstituted alkynyl preferably having 2 to about 12 carbon atoms,optionally substituted heteroalkyl preferably having from 1 to about 12carbon atoms particularly optionally substituted alkoxy preferablyhaving from 1 to about 12 carbon atoms, optionally substitutedheteroalkenyl preferably having from 2 to about 12 carbon atoms,optionally substituted heteroalkynyl preferably having from 2 to about12 carbon atoms; and

R⁴ and R⁵ are independently selected at each occurrence from the groupconsisting of hydrogen, optionally substituted alkyl preferably having 1to about 12 carbon atoms, optionally substituted cycloalkyl preferablyhaving 3 to about 8 ring carbon atoms, optionally substitutedheterocycloalkyl preferably having 3 to about 8 ring atoms at least oneof which is N, O or S optionally substituted alkenyl preferably having 2to about 12 carbon atoms, optionally substituted alkynyl preferablyhaving 2 to about 12 carbon atoms, optionally substituted heteroalkylpreferably having from 1 to about 12 carbon atoms particularlyoptionally substituted alkoxy preferably having from 1 to about 12carbon atoms, optionally substituted heteroalkenyl preferably havingfrom 2 to about 12 carbon atoms, optionally substituted heteroalkynylpreferably having from 2 to about 12 carbon atoms, optionallysubstituted carbocyclic aryl, optionally substituted heteroaryl,optionally substituted arylalkyl preferably aryl C₁₋₄alkyl, andoptionally substituted heteroarylalkyl preferably heteroaryl C₁₋₄alkyl;and pharmaceutically acceptable salts thereof.

In each of Formulae I, II, III and IV, preferably G is present at the3-position of the pyrrolidine ring. Also preferred are compounds wherethe 4- and 5-pyrrolidine ring positions are unsubstituted.

Preferred compounds of the invention also include those of the followingFormula V:

wherein

A is selected from O and CH₂;

B is CR²R³ or absent wherein R² and R³ are independently selected from Hand optionally substituted C₁-C₆ alkyl, preferably H; or A and B takenin combination form an optionally substituted 1,2-vinylene group;

G is halogen, particularly Cl or F, preferably Cl;

L is C(O)Z;

Q is (CR²R³)_(q) which may include 0 or 1 C═C double bond;

U is —CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl;

V is selected from (CR²R³)_(m), optionally substituted divalent aryl andoptionally substituted divalent heteroaryl;

W is selected from hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl C₁-C₆ alkyl, optionallysubstituted aryl and optionally substituted heteroaryl;

Z is hydroxy;

m is an integer selected from 1, 2, 3, 4, 5 and 6, preferably 3;

q is an integer selected from 0, 1, 2, 3, 4 and 5, preferably selectedfrom 1 and 2.

One more preferred group of compounds of the invention also includethose of the following Formula VI:

wherein

G is halogen, particularly Cl or F, preferably Cl;

L is C(O)Z;

Q is (CR²R³)_(q) wherein R² and R³ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H;

U is —CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl;

V is selected from optionally substituted divalent aryl and optionallysubstituted divalent heteroaryl, preferably aryl;

W is selected from hydrogen, optionally substituted C₁-C₆ alkyl andoptionally substituted C₃-C₆ cycloalkyl C₁-C₆ alkyl;

Z is hydroxy;

q is an integer selected from 1 and 2.

Another more preferred group of compounds of the invention also includethose of the following Formula VII:

wherein

B is CH₂ or absent;

G is halogen, particularly Cl or F, preferably Cl;

L is C(O)Z;

Q is (CR²R³)_(q) wherein R² and R³ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H;

U is —CR⁶R⁶7-W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl;

V is selected from optionally substituted divalent aryl and optionallysubstituted divalent heteroaryl;

W is selected from hydrogen, optionally substituted C₁-C₆ alkyl andoptionally substituted C₃-C₆ cycloalkyl C₁-C₆ alkyl;

Z is hydroxy,

q is an integer selected from 1 or 2, preferably 1.

Another more preferred group of compounds of the invention also includethose of the following Formula VIII:

wherein

G is halogen, particularly Cl or F, preferably Cl;

L is C(O)Z;

Q is (CR²R³)_(q) which may include 0 or 1 C═C double bonds wherein R²and R³ are independently selected from H and optionally substitutedC₁-C₆ alkyl, preferably H;

U is —CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl;

V is (CR²R³)_(m);

W is selected from hydrogen, optionally substituted C₁-C₆ alkyl andoptionally substituted C₃-C₆ cycloalkyl C₁-C₆ alkyl;

Z is hydroxy;

m is an integer selected from 1, 2 and 3, preferably 3;

q is an integer selected from 1 and 2, preferably 2.

Another more preferred group of compounds of the invention also includethose of the following Formula IX:

wherein

G is halogen, particularly Cl or F, preferably Cl;

L is C(O)Z;

Q is (CR²R³)_(q) wherein R² and R³ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H;

U is —CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl;

V is (CR²R³)_(m);

W is selected from optionally substituted aryl and optionallysubstituted heteroaryl, preferably aryl;

Z is hydroxy;

m is an integer selected from 1, 2 and 3, preferably 3;

q is an integer selected from 1 and 2, preferably 1.

Preferred compounds of the invention also include those of the followingFormula X:

wherein

A is selected from O and CH₂, preferably CH₂;

B is CR²R³ or absent wherein R² and R³ are independently selected from Hand optionally substituted C₁-C₆ alkyl, preferably H; or A and B takenin combination form an optionally substituted 1,2-vinylene group;

G is oxo;

L is C(O)Z;

Q is (CR²R³)_(q) which may include 0 or 1 C═C double bond;

U is —CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl;

V is selected from optionally substituted divalent aryl and optionallysubstituted divalent heteroaryl; or when A and B taken in combinationform an optionally substituted 1,2-vinylene group V is (CR²R³)_(m);

W is selected from hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl C₁-C₆ alkyl, optionallysubstituted aryl and optionally substituted heteroaryl;

Z is hydroxy;

m is an integer selected from 1, 2, 3, 4, 5 and 6, preferably 3;

q is an integer selected from 0, 1, 2, 3, 4 and 5, preferably selectedfrom 1 and 2.

Preferred compounds of the invention also include those of the followingFormula X′:

wherein

A is CH₂;

B is CR²R³ or absent wherein R² and R³ are independently selected from Hand optionally substituted C₁-C₆ alkyl, preferably H;

G is oxo;

L is C(O)Z;

Q is (CR²R³)_(q) which may include 0 or 1 C═C double bond;

U is —CR⁶R⁷—W wherein R⁶ and R⁷ form an optionally substitutedC₃-C₆cycloalkyl with the carbon they are attached to, preferably anoptionally substituted C₃or C₄ cycloalkyl;

V is selected from (CR²R³)_(m), optionally substituted divalent aryl andoptionally substituted divalent heteroaryl, preferably (CR²R³)_(m);

W is selected from hydrogen, optionally substituted C₁-C₆ alkyl andoptionally substituted C₃-C₆ cycloalkyl C₁-C₆ alkyl;

Z is hydroxy,

m is an integer selected from 1, 2, 3, 4, 5 and 6, preferably 3;

q is an integer selected from 0, 1, 2, 3, 4 and 5, preferably selectedfrom 1 and 2.

One more preferred group of compounds of the invention also includethose of the following Formula XI:

wherein

G is oxo;

L is C(O)Z;

Q is (CR²R³)_(q) wherein R² and R³ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H;

U is —CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl;

V is selected from optionally substituted divalent aryl and optionallysubstituted divalent heteroaryl, preferably aryl;

W is selected from hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl C₁-C₆; alkyl, preferablyoptionally substituted C₁-C₆ alkyl;

Z is hydroxy;

m is an integer selected from 1, 2 and 3, preferably 3;

q is an integer selected from 1 and 2, preferably 1.

Another more preferred group of compounds of the invention also includethose of the following Formula XII:

wherein

G is oxo;

L is C(O)Z;

Q is (CR²R³)_(q) wherein R² and R³ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H;

U is —CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl;

V is (CR²R³)_(m);

W is selected from optionally substituted aryl and optionallysubstituted divalent heteroaryl, preferably aryl;

Z is hydroxy;

m is an integer selected from 1, 2 and 3, preferably 3;

q is an integer selected from 1 and 2, preferably 1.

Preferred compounds of the invention include those of the followingFormula XIII:

wherein Q, U, A, B, V, L and G are the same as defined in Formula IVabove; and pharmaceutically acceptable salts thereof.

For at least some applications, particularly preferred compounds includethose of the following Formula XIV:

-   -   wherein    -   q is an integer from 1-3;    -   q′ is an integer from 2-4;    -   G is oxo, chloro, fluoro, methyl, methoxy;    -   Z is hydroxy, C₁₋₆alkoxy, amino or mono C₁₋₆alkylamino or di        C₁₋₆alkylamino; and    -   U is —(CR²R³)_(s)—W, wherein R² and R³ are independently the        same as those substituents are defined in Formula IV above;    -   s is an integer from 0-6, preferably 2-6; W is hydrogen or        C₃₋₇cycloalkyl; and pharmaceutically acceptable salts thereof.

Also, for at least some applications, particularly preferred compoundsinclude those of the following Formula XV:

-   -   wherein    -   A is O, S or CH₂;    -   B is CH₂ or absent    -   V is divalent phenyl, divalent furan, or divalent thiophene;    -   p is an integer from 1-3;    -   G is oxo, chloro, fluoro, methyl, methoxy;    -   Z is hydroxy, C₁₋₆alkoxy, amino or mono C₁₋₆alkylamino or di        C₁₋₆alkylamino;    -   U is —(CR²R³)_(s)—W, wherein R² and R³ are independently the        same as those substituents are defined in Formula IV above;    -   s is an integer from 0-6, preferably 2-6; and W is hydrogen or        C₃₋₇cycloalkyl; and pharmaceutically acceptable salts thereof.

The invention also includes compounds and use of optically activecompounds of the above Formulae, particularly compounds of the aboveFormulae I through XV where a single stereoisomer of a chiral compoundis present in an enaniomeric excess, e.g. where a single stereosiomer ispresent in an amount of at least 70 mole percent relative to otherstereosiomer(s), more preferably where one stereoisomer is present in anamount of at least about 80, 85, 90, 92, 93, 94, 95, 96, 97, 98 or 99mole percent relative to other stereosiomer(s).

Preferred compounds of the invention exhibit good binding activity in astandard prostaglandin EP2 and/or EP4 receptor binding assays. Such anassay is defined in Examples 22 and 24, which follows.

In an another aspect, the invention provides a coordinatedadministration regime of a substituted pyrrolidine compound with adistinct phosphodiesterase (PDE) inhibitor compound for simultaneous,sequential or separate use.

In a further aspect, the invention provides a coordinated administrationregime of a substituted pyrrolidine compound with a distinctphosphodiesterase (PDE) inhibitor compound. A coordinated regimetypically entails administration of a substituted pyrrolidine compoundsubstantially simultaneously with a phosphodiesterase inhibitor compound(cocktail formulation), or where the distinct therapeutics areadministered separately but within the same general time period, e.g.within the same 6, 12, 24, 48, 72, 96 or 120 hour period.

Without being bound by any theory, it is believed that such coordinatedadministration of a PDE inhibitor compound can provide increased cyclicGMP levels in a subject which can further enhance effects of theadministered substituted pyrrolidine compound.

A variety of PDE inhibitor compounds may be employed. A specificallypreferred pyrazolo[4,3-d]prymidin-7-one is sildenfil (Viagra™), alsoknown as5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3d]pyrimidin-7-one;as well as pharmaceutically acceptable salts thereof. Also preferred iszaprinast. Other preferred PDE inhibitors for use with the inventioninclude, but are not limited to, particular bicyclic heterocylic PDEinhibitors, more preferably pyrazolo[4,3-d]prymidin-7-ones,pryazolo[3,4-d]pyrimidin-4-ones, quinazolin-4-ones, purin-6-ones,pyrido[3,2-d]pyrimidin-4-ones; as well as pharmaceutically acceptablesalts thereof.

Still further examples of particular phosphodiesterase (PDE) inhibitorshave been previously reported in U.S. Pat. Nos. 6,100,270; 6,006,735;6,143,757; 6,143,746; 6,140,329; 6,117,881; 6,043,252; 6,001,847;5,981,527; and 6,207,829 B1; the disclosures of which patents areincorporated herein by reference. See also PCT/EP95/04065;WO-A-93/06104; WO-A-93/07149; WO-A-93/12095; WO-A-94/00453; EP 0 463756B1; and WO-A-94/05661 for additional compounds. See also U.S. Pat. Nos.4,753,945; 5,010,086; 6,121,279; 6,156,753; 6,054,475; 5,091,431;6,127,363 and 6,040,309 for additional compounds useful as nucleic aciddelivery agents in accordance with the invention. Additional PDEinhibitor compounds for use in accordance with the invention aredisclosed in Komas et al., Phosphodiesterase Inhibitors (1996) (Schudteds.), Academic Press, San Diego, Calif.

As discussed above, substituted pyrrolidine compounds of the inventionare useful for treatment of diseases and disorders associated with theprostaglandin family of compounds.

In a yet further aspect, the invention use of a substituted pyrrolidinecompound, including a compound of any one of Formulae I though XV forthe preparation of a medicament for the treatment or preventiontreatment of a mammal suffering from or susceptible to (prophylactictherapy) a disease or condition as disclosed herein including pre-termlabor, dysmenorrhea, asthma and other conditions treated bybronchodilation, inflammation, hypertension, undesired blood-clottingand other undesired platelet activities, pre-eclampsia and/or eclampsia,and eosinphil-related disorders and other diseases and disordersassociated with the prostaglandin EP2 and or EP4 receptor(s).Pyrrolidine compounds of the invention also are useful to treat a mammalsuffering from or suspected of suffering from infertility, particularlya female suffering from infertility. Pyrrolidine compounds of theinvention may be particularly beneficial for treatment of female mammalssuffering from an ovulatory disorder. Additionally, pyrrolidinecompounds of the invention can be administered to females undergoingreproductive treatments such as in-vitro fertilization or implantprocedures, e.g. to stimulate follicular development and maturation.Pyrrolidine compounds of the invention also are useful to treat sexualdysfunction, including erectile dysfunction.

Preferred pyrrolidine compounds of the invention also will be useful fortreatment of undesired bone loss (e.g. osteoporosis, particularly inwomen) or otherwise promoting bone formation and treatment of other bonediseases such as Paget's disease.

Therapeutic methods of the invention in general comprise administeringan effective amount of one or more substituted pyrrolidine compounds asdisclosed herein to a mammal in need thereof. As discussed above, inpreferred aspects of the invention, a substituted pyrrolidine compoundis administered in conjunction with one or more PDE inhibitor compounds.

In a further aspect, the invention provides a use of a substitutedpyrrolidine compound, including a compound of any one of Formulae Ithrough XV for the preparation of a medicament for the treatment orprevention (including prophylactic treatment) of a disease or conditionas disclosed herein, including infertility, preterm labor, asthma,hypertension, sexual dysfunction, osteoporosis and other destructivebone disease or disorder, inflammation, and other diseases and disordersassociated with prostaglandin. The invention also includes use of asubstituted pyrrolidine compound in, conjunction with one or more PDEinhibitor compounds for the treatment or prevention of such disease orcondition as disclosed herein.

In a yet further aspect, the invention provides a use of a substitutedpyrrolidine compound, including a compound of any one of Formulae Ithrough XV for the preparation of a medicament for the treatment orprevention (including prophylactic treatment) of a disease or conditionas disclosed herein, including infertility, preterm labor, asthma,hypertension, sexual dysfunction, osteoporosis and other destructivebone disease or disorder, inflammation, and other diseases and disordersassociated with prostaglandin. The invention also includes use of asubstituted pyrrolidine compound in conjunction with one or more PDEinhibitor compounds for simultaneous, sequential or separate use, forthe preparation of a medicament for the treatment or prevention of suchdisease or condition as disclosed herein.

The invention also provides pharmaceutical compositions that compriseone or more substituted pyrrolidine compounds of the invention and asuitable carrier for the compositions, optionally formulated or packagedwith one or more PDE inhibitor compounds. Other aspects of the inventionare disclosed infra.

Other aspects of the invention are disclosed infra.

DETAILED DESCRIPTION OF THE INVENTION

We have now discovered that substituted pyrrolidine compounds, includingcompounds of the above Formulae I, II, III, IV, V, VI, VII, VIII, IX, X,XI, XII, XIII, XIV and XV are useful for treatment of a variety ofdisorders, particularly diseases and disorders associated withprostaglandin, such as by inhibiting prostanoid-induced smooth musclecontraction.

As discussed above, preferred compounds of the invention are substitutedat both the 2 and 3-ring positions in addition to N-substitution, butare unsubstituted at the 4- and 5-positions of the pyrrolidine ring,such as compounds of the following Formulae IA, IIA and IIIA:

wherein the substituents G, R, Y, U, U′, A, B, V and L are the same asdefined in Formulae I through III above.

Suitable alkyl substituent groups of compounds of the invention (whichincludes compounds of Formulae I, IA, II, IIA, III, IIIA, IV, V, X,XIII, XIV and XV as those formulae are defined above) typically havefrom 1 to about 12 carbon atoms, more preferably 1 to about 8 carbonatoms, still more preferably 1, 2, 3, 4, 5, or 6 carbon atoms. As usedherein, the term alkyl unless otherwise modified refers to both cyclicand noncyclic groups, although of course cyclic groups will comprise atleast three carbon ring members. Preferred alkenyl and alkynyl groups ofcompounds of the invention have one or more unsaturated linkages andtypically from 2 to about 12 carbon atoms, more preferably 2 to about 8carbon atoms, still more preferably 2, 3, 4, 5, or 6 carbon atoms. Theterms alkenyl and alkynyl as used herein refer to both cyclic andnoncyclic groups, although straight or branched noncyclic groups aregenerally more preferred. Preferred alkoxy groups of compounds of theinvention include groups having one or more oxygen linkages and from 1to about 12 carbon atoms, more preferably from 1 to about 8 carbonatoms, and still more preferably 1, 2, 3, 4, 5 or 6 carbon atoms.Preferred alkylthio groups of compounds of the invention include thosegroups having one or more thioether linkages and from 1 to about 12carbon atoms, more preferably from 1 to about 8 carbon atoms, and stillmore preferably 1, 2, 3, 4, 5, or 6 carbon atoms. Preferredalkylsulfinyl groups of compounds of the invention include those groupshaving one or more sulfoxide (SO) groups and from 1 to about 12 carbonatoms, more preferably from 1 to about 8 carbon atoms, and still morepreferably 1, 2, 3, 4, 5, or 6 carbon atoms. Preferred alkylsulfonylgroups of compounds of the invention include those groups having one ormore sulfonyl (SO₂) groups and from 1 to about 12 carbon atoms, morepreferably from 1 to about 8 carbon atoms, and still more preferably 1,2, 3, 4, 5 or 6 carbon atoms. Preferred aminoalkyl groups include thosegroups having one or more primary, secondary and/or tertiary aminegroups, and from 1 to about 12 carbon atoms, more preferably 1 to about8 carbon atoms, still more preferably 1, 2, 3, 4, 5, or 6 carbon atoms.Secondary and tertiary amine groups are generally more preferred thanprimary amine moieties. Suitable heteroaromatic groups of compounds ofthe invention contain one or more N, O or S atoms and include, e.g.,coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl,pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl thienyl, thiazolyl,oxazolyl, oxidizolyl, triazole, imidazolyl, indolyl, benzofuranyl andbenzothiazole. Suitable heteroalicyclic groups of compounds of theinvention contain one or more N, O or S atoms and include, e.g.,tetrahydrofuranyl, thienyl, tetrahydropyranyl, piperidinyl, morpholinoand pyrrodinyl groups. Suitable carbocyclic aryl groups of compounds ofthe invention include single and multiple ring compounds, includingmultiple ring compounds that contain separate and/or fused aryl groups.Typical carbocyclic aryl groups of compounds of the invention contain 1to 3 separate or fused rings and from 6 to about 18 carbon ring atoms.Specifically preferred carbocyclic aryl groups include phenyl; naphthylincluding 1-naphthyl and 2-naphthyl; biphenyl; phenanthryl; anthracyl;and acenaphthyl. Substituted carbocyclic groups are particularlysuitable including substituted phenyl, such as 2-substituted phenyl,3-substituted phenyl, 4-substituted phenyl, 2,3-substituted phenyl,2,4-substituted phenyl, and 2,5-substituted phenyl; and substitutednaphthyl, including naphthyl substituted at the 5, 6 and/or 7 positions.

Suitable aralkyl groups of compounds of the invention include single andmultiple ring compounds, including multiple ring compounds that containseparate and/or fused aryl groups. Typical aralkyl groups contain 1 to 3separate or fused rings and from 6 to about 18 carbon ring atoms.Preferred aralkyl groups include benzyl and methylenenaphthyl(—CH₂-naphthyl), and other carbocyclic aralkyl groups, as discussedabove.

Suitable heteroaralkyl groups of compounds of the invention includesingle and multiple ring compounds, including multiple ring compoundsthat contain separate and/or fused heteroaromatic groups, where suchgroups are substituted onto an alkyl linkage. More preferably, aheteroaralkyl group contains a heteroaromatic group that has 1 to 3rings, 3 to 8 ring members in each ring and from 1 to 3 hetero (N, O orS) atoms, substituted onto an alkyl linkage. Suitable heteroaromaticgroups substituted onto an alkyl linkage include e.g., coumarinylincluding 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl,pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyloxidizolyl, triazole, imidazolyl, indolyl, benzofuranyl andbenzothiazole.

Suitable heteroalicyclicalkyl groups of compounds of the inventioninclude single and multiple ring compounds, where such groups aresubstituted onto an alkyl linkage. More preferably, aheteroalicylicalkyl group contains at least one ring that has 3 to 8ring members from 1 to 3 hetero (N, O or S) atoms, substituted onto analkyl linkage. Suitable heteroalicyclic groups substituted onto an alkyllinkage include e.g. tetrahydrofuranyl, thienyl, tetrahydropyranyl,piperidinyl, morpholino and pyrrolidinyl groups.

The term “C₁-C₆-alkyl” refers to monovalent branched or unbranched alkylgroups having 1 to 5 carbon atoms. This term is exemplified by groupssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl isobutyl,tert-butyl, n-hexyl and the like.

The term “C₃-C₆-cycloalkyl C₁-C₆-alkyl” refers to C₁-C₆-alkyl groups, asdefined above, having saturated carbocyclic rings having 3 to 6 carbonatoms as substituant. Examples include ethyl cyclobutyl,cyclopropylmethyl cyclobutyl and the like.

The term “C₃-C₆-cycloalkyl” refers to saturated carbocyclic rings having3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl and the like.

The term “Aryl” refers to aromatic carbocyclic groups of from 6 to 14carbon atoms having a single ring (e.g. phenyl) or multiple condensedrings (e.g. naphthyl). Examples include phenyl, naphthyl, phenanthrenyland the like.

The term “Heteroaryl” refers to a monocyclic heteroaromatic, or abicyclic or a tricyclic fused-ring heteroaromatic group containing atleast one heteroatom selected from S, N and O. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl,1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl benzotriazolyl,isobenzothienyl, indolyl, isoindolyl 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzodioxolyl,quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnnolinyl,napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl,5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetra-hydroisoquinolyl, purinyl,pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

The term “heteroalkyl” as used herein is inclusive of alkoxy, alkylthio,alkylamino, alkylsulfinyl and alkylsulfonyl. The term “heteroalkenyl” asused herein is inclusive of such alkoxy, alkylthio, alkylamino,alkylsulfinyl and alkylsulfonyl groups that further include one or morecarbon-carbon double bonds, typically one or two carbon-carbon doublebonds. The term “heteroalkynyl” as used herein is inclusive of suchalkoxy, alkylthio, alkylamino, alkylsulfinyl and alkylsulfonyl groupsthat further include one or more carbon-carbon triple bonds, typicallyone or two carbon-carbon triple bonds.

As discussed above, various substituents of the above formulae, such asR, Y, G, R¹, R², R³, R⁴, R⁵, U, U′, A, B, V, L, Q, and Z may beoptionally substituted. A “substituted” R, Y, G, R¹, R², R³, R⁴, R⁵, U,U′, A, B, V, L, Q, and Z group or other substituent may be substitutedby other than hydrogen at one or more available positions, typically 1to 3 or 4 positions, by one or more suitable groups such as thosedisclosed herein. Suitable groups that may be present on a “substituted”R, Y, G, R¹, R², R³, R⁴, R⁵, U, U′A, B, V, L, Q, and Z group or othersubstituent include e.g. halogen such as fluoro, chloro, bromo and iodo;cyano; hydroxyl; nitro; azido; alkanoyl such as a C₁-C₆ alkanoyl groupsuch as acyl and the like; carboxamido; alkyl groups including thosegroups having 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbonatoms; alkenyl and alkynyl groups including groups having one or moreunsaturated linkages and from 2 to about 12 carbon, or 2, 3, 4, 5 or 6carbon atoms; alkoxy groups including those having one or more oxygenlinkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6carbon atoms; aryloxy such as phenoxy; alkylthio groups including thosemoieties having one or more thioether linkages and from 1 to about 12carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; alkylsulfinyl groupsincluding those moieties having one or more sulfinyl linkages and from 1to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms;alkylsulfonyl groups including those moieties having one or moresulfonyl linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5,or 6 carbon atoms; aminoalkyl groups such as groups having one or more Natoms and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbonatoms; carbocyclic aryl having 6 or more carbons; aralkyl having 1 to 3separate or fused rings and from 6 to about 18 carbon ring atoms, withbenzyl being a preferred group; aralkoxy having 1 to 3 separate or fusedrings and from 6 to about 18 carbon ring atoms, with O-benzyl being apreferred group; or a heteroaromatic or heteroalicyclic group having 1to 3 separate or fused rings with 3 to about 8 members per ring and oneor more N, O or S atoms, e.g. coirmarinyl, quinolinyl pyridyl,pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholino and pyrrolidinyl.

It should be understood that alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl and aminoalkyl substituent groups described above includegroups where a hetero atom is directly bonded to a ring system, such asa carbocyclic aryl group or heteroaromatic group or heteroalicyclicgroup including pyrrolidine group, as well as groups where a hetero atomof the group is spaced from such ring system by an alkylene linkage,e.g. of 1 to about 4 carbon atoms.

A particularly preferred embodiment of the invention is pyrrolidinederivatives according to formula VI wherein G is halogen, including Clor F, preferably Cl; V is selected from optionally substituted divalentaryl and optionally substituted divalent heteroaryl, preferably aryl,more preferably phenyl; L is —C(O)OH; Q is (CR²R³)_(q) wherein R² and R³are independently selected from H and optionally substituted C₁-C₆alkyl, preferably H; q is an integer selected from 1 and 2; U is—CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl,more preferably cyclobutyl; W is selected from hydrogen, optionallysubstituted C₁-C₆ alkyl and optionally substituted C₃-C₆ cycloalkylC₁-C₆ alkyl, preferably optionally substituted C₁-C₆ alkyl, morepreferably butyl.

Another particularly preferred embodiment of the invention ispyrrolidine derivatives according to formula VII wherein G is halogen,including Cl or F, preferably Cl; B is CH₂ or absent; V is selected fromoptionally substituted divalent aryl and optionally substituted divalentheteroaryl, more preferably phenyl or furanyl; L is —C(O)OH; Q is(CR²R³)_(q) wherein R² and R³ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; q is an integerselected from 1 or 2, preferably 1; U is —CR⁶R⁷—W, wherein R⁶ and R⁷ areindependently selected from H and optionally substituted C₁-C₆ alkyl,preferably H; or R⁶ and R⁷ can form an optionally substituted C₃-C₆cycloalkyl with the carbon they are attached to, preferably anoptionally substituted C₃ or C₄ cycloalkyl, more preferably cyclobutyl;W is selected from hydrogen, optionally substituted C₁-C₆ alkyl andoptionally substituted C₃-C₆cycloalkyl C₁-C₆ alkyl, preferablyoptionally substituted C₁-C₆ alkyl, more preferably butyl.

Another particularly preferred embodiment of the invention ispyrrolidine derivatives according to formula VII wherein G is halogen,including Cl or F, preferably Cl; V is (CR²R³)_(m), preferably(CH₂)_(m); m is an integer selected from 1, 2 and 3, preferably 3; L is—C(O)OH; Q is (CR²R³)_(q) wherein R² and R³ are independently selectedfrom H and optionally substituted C₁-C₆ alkyl, preferably H; q is aninteger selected from 1 and 2, preferably 1; U is —CR⁶R⁷—W, wherein R⁶and R⁷ are independently selected from H and optionally substitutedC₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can form an optionallysubstituted C₃-C₆ cycloalkyl with the carbon they are attached to,preferably an optionally substituted C₃ or C₄ cycloalkyl, morepreferably cyclobutyl; W is selected from hydrogen, optionallysubstituted C₁-C₆ alkyl and optionally substituted C₃-C₆ cycloalkylC₁-C₆ alkyl, preferably methyl cyclopropyl, ethyl, propyl and butyl.

Another particularly preferred embodiment of the invention ispyrrolidine derivatives according to formula IX wherein G is halogen,including Cl or F, preferably Cl; V is (CR²R³)_(m), preferably(CH₂)_(m); m is an integer selected from 1, 2 and 3, preferably 3; L is—C(O)OH; Q is (CR²R³)_(q) wherein R² and R³ are independently selectedfrom H and optionally substituted C₁-C₆ alkyl, preferably H; q is aninteger selected from 1 or 2, preferably 1; U is —CR⁶R⁷—W, wherein R⁶and R⁷ are independently selected from H and optionally substitutedC₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can form a C₂-C₆ cycloalkyl withthe carbon they are attached to, preferably an optionally substituted C₃or C₄ cycloalkyl, more preferably cyclopropyl; W is selected fromoptionally substituted aryl and optionally substituted divalentheteroaryl, preferably aryl, more preferably optionally substitutedphenyl, including 3-methyl phenyl and unsubstituted phenyl.

Another particularly preferred embodiment of the invention ispyrrolidine derivatives according to formula X′ wherein G is oxo; A isCH₂; V is selected from (CR²R³)_(m), optionally substituted aryl andoptionally substituted heteroaryl, preferably (CH₂)_(m); is an integerselected from 1, 2, 3, 4, 5 and 6, preferably 3; L is —C(O)OH; Q is(CR²R³)_(q) wherein R² and R³ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; q is selected from 1and 2, preferably 1; U is —CR⁶R⁷—W, wherein R⁶ and R⁷ form an optionallysubstituted C₃-C₆ cycloalkyl with the carbon they are attached to,preferably an optionally substituted C₃ or C₄ cycloalkyl, morepreferably cyclopropyl; W is selected from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl C₁-C₆alkyl, preferably methyl cyclopropyl;

Another particularly preferred embodiment of the invention ispyrrolidine derivatives according to formula XI wherein G is oxo; V is(CR²R³)_(m), preferably (CH₂)_(m); m is an integer selected from 1, 2and 3, preferably 3; L is —C(O)OH; Q is (CR²R³)_(q) wherein R² and R³are independently selected from H and optionally substituted C₁-C₆alkyl, preferably H; q is selected from 1 and 2, preferably 1; U is—CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from H andoptionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ can forman optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl,more preferably cyclopropyl; W is selected from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl C₁-C₆alkyl, optionally substituted C₃-C₆ cycloalkyl, preferably C₃-C₆cycloalkyl C₁-C₆ alkyl, more preferably methyl cyclopropyl;

Another particularly preferred embodiment of the invention ispyrrolidine derivatives according to formula XII wherein G is oxo; V is(CR²R³)_(m), preferably (CH₂)_(m); m is an integer selected from 1, 2and 3, preferably 3; L is —C(O)OH; Q is (CR²R³)_(q) wherein R² and R³are independently selected from H and optionally substituted C₁-C₆alkyl, preferably H; q is an integer selected from 1 and 2, preferably1; U is —CR⁶R⁷—W, wherein R⁶ and R⁷ are independently selected from Hand optionally substituted C₁-C₆ alkyl, preferably H; or R⁶ and R⁷ canform an optionally substituted C₃-C₆ cycloalkyl with the carbon they areattached to, preferably an optionally substituted C₃ or C₄ cycloalkyl,more preferably cyclopropyl; W is selected from optionally substitutedaryl and optionally substituted divalent heteroaryl, preferably aryl,more preferably optionally substituted phenyl, including 3-methyl phenyland unsubstituted phenyl;

Specifically preferred substituted pyrrolidine compounds of theinvention include the following depicted compounds, and pharmaceuticallyacceptable salts of these compounds.

As discussed above, preferred compounds of the invention exhibit goodactivity in a standard prostaglandin EP2 and or EP4 receptor bindingassay. References herein to “standard prostaglandin EP2 receptor bindingassay” are intended to refer to the protocol as defined in Example 22,which follows. References herein to “standard prostaglandin EP2 receptorbinding assay” are intended to refer to the protocol as defined inExample 24, which follows.

Generally preferred compounds of the invention have a Ki (μM) of about100 or less, more preferably about 50 or less, still more preferably aKi (μM) of about 10 or 20or less, even more preferably a Ki (μM) ofabout 5 or less in such a defined standard prostaglandin assay asexemplified by Examples 22 and 24 which follow.

Abbreviations

The following abbreviations are hereinafter used in the accompanyingexamples:

min (minute), hr (hour), g (gram), mmol (millimole), ml (milliliter), μl(microliters), ACN (acetonitrile), DCM (dichloromethane), DMAP(4-dimethylamino-pyridine), DMSO (dimethyl sulfoxide), EtOAc (ethylacetate), LDA (Lithium diisopropylamide), RT (room temperature), TBAF(Tetrabutylammonium fluoride), TFA (trifluoro-acetic acid), THF(tetrahydrofuran), TLC (Thin Layer Chromatography).

Synthesis of Compounds of the Invention:

Pyrrolidine compounds of the invention can be readily prepared fromreadily available starting materials using the following general methodsand procedures.

Suitable synthetic procedures are exemplified in the followingillustrative Schemes 1, 2, 3 and 4. It should be appreciated that thecompounds shown in the following Schemes are exemplary only, and avariety of other compounds can be employed in a similar manner asdescribed below. For instance, pyrrolidine compounds having non-hydrogensubstituents at 4 and 5 ring positions can be provided using a startingreagent having such substitution. It will also be appreciated that wheretypical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used. Such conditions can be determined by the person skilledin the art, using routine optimisation procedures.

General Protocol:

Referring now to Scheme 1 below, hydrogenation of the pyrrolidineintermediate i (which was prepared according to the procedure ofMacdonald et al: J. Med. Chem. 1998, 41(21), 3919-3922) followed byreaction with di-tert-butyl dicarbonate can give the desired pyrrolidinederivatives ii bearing the Boc group on the nitrogen of the pyrrolidinering. Reduction of the methyl ester group e.g. using Red-Al in asuitable solvent such as benzene or other aromatic solvent preferably atelevated temperature can provide alcohol intermediate iii typically inhigh yield. Oxidation of the alcohol such as by Swern methodology cangive corresponding aldehyde which can be further functionalized e.g. byWittig reaction as shown in Scheme 1 using(4-carboxybutyl)triphenylphosphonium bromide and KotBu or other suitablebase. The acid intermediate can be esterified such as by treatment withtrimethylsylildiazomethane to provide ester intermediate iv.

The silyl protecting group may be suitably removed with fluoride ion,e.g. using TBAF in a suitable solvent such as THF to provide alcohol vwhich in rum can be oxidized such as by Swern methodology. The ketoneintermediate is then suitably protected as ketal e.g. using trimethylorthoformate and H₂SO₄ in MeOH. Those reactions conditions also providedN-deprotection was also accomplished and the intermediate vi wasobtained in good yield. The compound may be resolved by suitable meansincluding fractional crystallization using appropriate optically activereagents such as D-tartaric acid and i-PrOH. Chiral chromatography alsocould be employed.

For the preparation of the 16-hydroxy pyrrolidine derivatives, thechiral amine intermediate vii can undergo Michael's reaction with thedesired 2,3 unsaturated ketone to provide the product intermediate viiitypically in quite high yields. Reduction of the ketone (e.g. Luche'sreduction) followed by hydrolysis preferably under acidic conditions canprovide pyrrolidine derivative ix.

Preparation of pyrrolidine compounds bearing the hydroxyl group inposition 17 can be obtained by reductive amination reaction of thepyrrolidine intermediate vii with the appropriate aldehyde and NaCNBH₃in MeOH. Treatment of the intermediate x with HCl 4M in dioxane canresult in deprotection of both ketal and O-silyl groups. Saponificationof the ester xi gave the desired acid xii in good yields. Example 5below particularly exemplifies this general approach.

For the preparation of the saturated derivatives xiv, the esterintermediate of general formula xi was hydrogenated at 1 atm using Pd/Cin MeOH (Step N). Saponification of the ester xiii using NaOH gave thecorrespondent acid xiv in good yield. Example 19 below particularlyexemplifies this general approach.

Referring now to Scheme 2 below, alcohol i (suitably obtained asdescribed in Scheme 1 above, intermediate v) can be activated such as byforming a sulfonyl ester, e.g. by reaction with tosyl chloride in thepresence of pyridine or other base to afford the tosylate intermediateii. That 3-position of the pyrrolidine ring can be then furtherfunctionalized as desired by nucleophilic substitution such as bytreatment with tetrabutylammonium chloride in toluene or other suitablesolvent to provide the depicted 3-chloro pyrrolidine compound. Aciddeprotection using HCl in dioxane can provide pyrrolidine intermediateiii. Preparation of the further 16-hydroxy or 17-hydroxy pyrrolidinecompounds can be accomplished as described with respect to Scheme 1(steps G, H and I, L, M, respectively) above using the pyrrolidinederivative iii. Example 1 below particularly exemplifies this generalapproach of Scheme 2.

Preparation of compounds having the double bond in position 14(prostaglandin numbering) can be obtained by N-alkylation of thepyrrolidine intermediate iii with the desired allyl bromide derivatives.Deprotection of the alcohol using standard acidic condition followed bysaponification reaction (step E and F respectively) afford the desiredproduct xii. Example 3 below particularly exemplifies this generalapproach of Scheme 2.

Referring now to Scheme 3 below, reduction of the pyrrolidineintermediate ii (which was prepared from GlyOEt according to theprocedure described in J. Chem. Soc. Perkin Trans. 1, 1993, 1313-1317)e.g. with L-selectride can give the depicted cis alcohol derivative iii.The same reduction can also be carried out with baker's yeast to affordthe desired chiral cis alcohol iii. The 3-positon of the pyrrolidinering can be substituted to provide a variety of groups, e.g. oxidized toprovide an oxo (>C═O) ring atom, or the ring carbon can be substitutedthrough a nucleophilic displacement. Thus, as shown in Scheme 3, thealcohol iii can be tosylated followed by reaction withtetrabutylammonium chloride can provide the 3-chloro pyrrolidinederivative iv. Reduction of the ester group using NaBH₄ in THF/MeOH(9/1) gave the alcohol intermediate v.

Preparation of the corresponding phenyl ether derivatives (viii) wasobtained via Mitsunobu reaction between the alcohol v and theappropriate phenol derivatives. The ethers or thioethers derivative vithen can be converted to the corresponding 16-hydroxy or 17-hydroxypyrrolidine compounds as generally described with respect to Scheme 1.

Synthesis of the phenethyl derivatives of general formula xii can beobtained by Wittig reaction between the aldehyde intermediate obtainede.g. by Swern oxidation of the alcohol v and the desired phosphoranederivatives. Catalytic hydrogenation followed by acid deprotection canprovide the pyrrolidine intermediate x. Synthesis of the corresponding16-hydroxy and 17-hydroxy pyrrolidine compounds can be obtained asdescribed above with respect to Scheme 1.

Preparation of the furyl ether derivatives of general formula xiv can beobtained by alkylation of the alcohol v with the appropriate bromideusing a strong base such as NaH in DMF. The intermediate xiii then canbe converted to the desired pyrrolidine derivatives using protocolsdescribed above.

Examples 6-8 below particularly exemplify this general approach ofScheme 3.

Referring now to Scheme 4 below, which shows a preferred route tocompounds of Formula IX and XII above, a deprotection reaction of thepyrrolidine intermediate (which can be prepared according to theprocedure of Macdonald et al: J. Med. Chem. 1998, 41(21), 3919-3922)followed by reaction with di-tert-butyl dicarbonate gives the desiredpyrrolidine derivatives bearing the Boc group on the nitrogen of thepyrrolidine ring (ii).

Reduction of the methyl ester group using Red-Al in suitable solventsuch as an aromatic solvent e.g. benzene at reflux or other elevatedtemperature can provide alcohol intermediate iii in almost quantitativeyield. Oxidation of the alcohol moiety e.g. using the traditional Swernmethodology can provide the corresponding aldehyde mat can be used in aWittig reaction with (4-carboxybutyl)triphenylphosphonium bromide andsuitable base such as KOtBu. The free acid intermediate is suitablyprotected in situ e.g. as methyl ester using tri-methylsylildiazomethaneto lead to intermediate iv. Removal of the silyl group using fluoridesuch TBAF in THF can give the alcohol v that is oxidized e.g using theSwern methodology, followed by protecting the ketone intermediate e.g.as a ketal using trimethyl orthoformate and H₂SO₄ in MeOH. Under suchreaction conditions, N-deprotection also can result thereby providingintermediate vi. The racemic mixture can be resolved, e.g. by fractionalcrystallization using D-tartaric acid in i-PrOH. Intermediate vii canundergo Michael addition with suitable electrophile such as the depicted2,3-unsaturated ketone to provide the ketone intermediate viii in almostquantitative yield. Luche reduction of the ketone followed by acidhydrolysis can provide in good yield the desired pyrrolidine derivativesix.

Preparation of the depicted 3-chloro pyrrolidine derivatives can beaccomplished starting from the alcohol intermediate v. Replacement ofthe alcohol function with chloro can be obtained in a two-step procedurevia activation of intermediate x e.g. the preparation of the tosylateintermediate x. Displacement of the tosyl group can be accomplishedusing tetrabutylammonium chloride in toluene at 50-60° C. Deprotectionof the nitrogen atom using HCl in dioxane can give in quantitative yieldthe desired intermediate xi. Michael reaction with the desiredunsaturated ketone can yield xii in good yield. Luche's reductionfollowed by saponification of the methyl ester intermediate can providethe desired pyrrolidine derivatives xiii. Examples 12 through 14 belowparticularly exemplify this general approach.

Additional preferred syntheses of compounds of the invention aredetailed in the examples which follow.

As discussed above, a preferred aspect of the invention includescoordinated administration of a substituted pyrrolidine compound, suchas a compound of any one of Formulae I through XV, with one or more PDEinhibitor compounds.

In addition to the PDE inhibitor compounds discussed above, suitable PDEinhibitor compounds for use in the methods and compositions of theinvention are disclosed below, including compounds of the followingFormulae XVI to XXIII, which are generally preferred for use with thepresent invention. It should be appreciated however that the presentinvention is not limited by any particular PDE inhibitor compound, andthe invention is applicable to any such PDE inhibitor compound now knownor subsequently discovered or developed. As discussed below, in additionto the PDE inhibitor compounds specifically identified herein, suitablePDE inhibitor compounds also may be identified by simple testing.

In general, PDE-5 inhibitor compounds are preferred for use in themethods and compositions of the invention.

More specifically, in one invention embodiment, at least one of theadministered compounds is a bicyclic heterocyclic PDE inhibitor such asdescribed in the U.S. Pat. No. 6,100,270, preferably at least one of thefollowing pyrazolo[4,3-d]prymidin-7-ones,pryazolo[3,4-d]pyrimidin-4-ones, a quinazolin-4-ones, a purin-6-ones, orpyrido[3,2-d]pyrimidin-4-ones set forth in the following Formulae I-Vincluding pharmaceutically acceptable salts thereof.

Suitable PDE inhibitor compounds include those of the following FormulaXVI:

wherein in Formula XVI, R¹ is methyl or ethyl; R² is ethyl or n-propyl;and R³ and R⁴ are each independently H, or C₁-C₆ alkyl optionallysubstituted with C₅-C₇ cycloalkyl or with morpholino; andpharmaceutically acceptable salts thereof.

Suitable PDE inhibitor compounds also include those of the followingFormula XVII:

wherein in Formula IX is C₁-C₆ alkyl; R² is H; methyl or ethyl;

R³ is C₂-C₄ alkyl;

R⁴ is H; C₁-C₄ alkyl optionally substituted with NR⁵R⁶, CN, CONR⁵R⁶ orCO₂R⁷; C₂-C₄ alkenyl optionally substituted with CN, CONR⁵R⁶ or CO₂R⁷;C₂-C₄ alkanoyl optionally substituted with NR⁵R⁶; SO₂NR⁵R⁶; CONR⁵R⁶;CO₂R⁷ or halo;

R⁵ and R⁶ are each independently H or C₁-C₄ alkyl; or, together with thenitrogen atom to which they are attached, form a pyrrolidino,piperidino, morpholino, 4-(NR⁸)-1-piperazinyl or 1-imidazolyl groupwherein said group is optionally substituted with one or two C₁-C₄ alkylgroups;

R⁷ is H or C₁-C₄ alkyl;

and R⁸ is H; C₁-C₃ alkyl or (hydroxy)C₂-C₃ alkyl; and pharmaceuticallysalts thereof.

Additional suitable PDE inhibitor compounds include those of thefollowing Formula (XVIII):

wherein in Formula XVIII R¹ is H; C₁-C₄ alkyl; C₁-C₄ alkoxy or CONR⁵R⁶;R² is H or C₁-C₄ alkyl;R³ is C₂-C₄ alkyl;R⁴ is H; C₂-C₄ alkanoyl optionally substituted with NR⁷R⁸;(hydroxy)C₂-C₄ alkyl optionally substituted with NR⁷R⁸; CH═CHCO₂R⁹;CH═CHCONR⁷R⁸; CH₂CH₂CO₂R⁹; CH₂CH₂CONR⁷R⁸; SO₂NR⁷R⁸; SO₂NH(CH₂)_(n)NR⁷R⁸or imidazolyl;R⁵ and R⁶ are each independently H or C₁-C₄ alkyl;R⁷ and R⁸ are each independently H or C₁-C₄ alkyl; or, together with thenitrogen atom to which they are attached, form a pyrrolidino,piperidino, morpholino or 4-(NR¹⁰)-1-piperazinyl group wherein any ofsaid groups is optionally substituted with CONR⁵R⁶;R⁹ is H or C₁-C₄ alkyl;R¹⁰ is H; C₁-C₃ alkyl or (hydroxy)C₂-C₃ alkyl;and n is 2, 3 or 4;preferably with the proviso that R⁴ is not H when R¹ is H, C₁-C₄ alkylor C₁-C₄ alkoxy; and pharmaceutically acceptable salts thereof.

Suitable PDE inhibitor compounds include those of the following FormulaXIX:

wherein in Formula XIX R¹ is C₁-C₄ alkyl; R² is C₂-C₄ alkyl;

R³ is H or SO₂NR⁴R⁵;

R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a pyrrolidino, piperidino, morpholino or 4-(NR⁶)-1-piperazinylgroup;and R⁶ is H or C₁-C₃ alkyl; and pharmaceutically acceptable saltsthereof.

Additional suitable PDE inhibitor compounds include those of thefollowing Formula (XX):

wherein in Formula XX R¹ is H; C₁-C₄ alkyl; CN or CONR⁴R⁵; R² is C₂-C₄alkyl;R³ is SO₂ NR⁶R⁷; NO₂; NH₂; NHCOR⁸; NHSO₂R⁸ or N(SO₂R⁸)₂;R⁴ and R⁵ are each independently selected from H and C₁-C₄ alkyl;R⁶ and R⁷ are each independently selected from H and C₁-C₄ alkyloptionally substituted with CO₂ R⁹, OH, pyridyl, 5-isoxazolin-3-onyl,morpholino or 1-imidazolidin-2-onyl or, together with the nitrogen atomto which they are attached, form a pyrrolidino, piperidino, morpholino,1-pyrazolyl or 4-(NR¹⁰)-1-piperazinyl group wherein any of said groupsmay optionally be substituted with one or two substituents selected fromC₁-C₄ alkyl, CO₂ R⁹, NH₂ and OH;R⁸ is C₁-C₄ alkyl or pyridyl;R⁹ is H or C₁-C₄ alkyl;and R¹⁰ is H; C₁-C₄ alkyl or (hydroxy)C₂-C₃ alkyl; and apharmaceutically acceptable salt thereof.

A preferred group of compounds of Formula XVI above include thosewherein:

R³ is H; methyl or ethyl;R⁴ is C₁-C₆ alkyl optionally substituted with cyclohexyl or withmorpholino; and pharmaceutically acceptable salts thereof.

Preferred compounds of Formula XVII above include those wherein R¹ isn-propyl; R² is H or methyl; R³ is ethyl or n-propyl; R⁴ is H; ethylsubstituted with CONR⁵R⁶ or CO₂R⁷; vinyl substituted with CONR⁵R⁶ orCO₂R⁷; acetyl substituted with NR⁵R⁶; SO₂NR⁵R⁶; CONR⁵R⁶; CO₂R⁷ or bromo;R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a morpholino, 4-(NR⁸)-1-piperazinyl or 2,4-dimethyl-1-imidazolylgroup; R⁷ is H or t-butyl; and R⁸ is methyl or 2-hydroxyethyl; andpharmaceutically acceptable salts thereof.

Preferred compounds of Formula XVIII above include those where R¹ is H;methyl; methoxy or CONR⁵R⁶; R² is H or methyl; R³ is ethyl or n-propyl;R⁴ is H; acetyl optionally substituted with NR⁷R⁸; hydroxyethylsubstituted with NR⁷R⁸; CH═CHCO₂ R⁹; CH═CHCONR⁷R⁸; CH₂CH₂CO₂R⁹;SO₂NR⁷R⁸; SO₂NH(CH₂)₃NR⁷R⁸ of 1-imidazolyl; R⁵ and R⁶ are eachindependently H or ethyl; R⁷ and R⁸ together with the nitrogen atom towhich they are attached form a piperidino, 4-carbamoylpiperidino,morpholino or 4-(NR¹⁰)-1-piperazinyl group; R⁹ is H or t-butyl; and R¹⁰is H; methyl or 2-hydroxyethyl; and pharmaceutically acceptable saltsthereof.

Preferred compounds of Formula XIX above include those wherein R¹ and R²are each independently ethyl or n-propyl; R⁴ and R⁵ together with thenitrogen atom to which they are attached form a 4-(NR⁶)-1-piperazinylgroup; and R³ and R⁶ are as previously defined for Formula XI; andpharmaceutically acceptable salts thereof.

Preferred compounds of Formula XX above include compounds wherein R¹ isH; n-propyl; CN or CONH₂; R² is ethyl; R³ is SO₂NR⁶R⁷; NO₂; NH₂;NHCOCH(CH₃)₂; NHSO₂CH(CH₃)₂; NHSO₂(3-pyridyl) or N[SO₂(3-pyridyl)]₂; R⁶is H; methyl or 2-hydroxyethyl; R⁷ is methyl optionally substituted with2-pyridyl or 5-isoxazolin-3-onyl; or ethyl 2-substituted with OH,CO₂CH₂CH₃, morpholino or 1-imidazolidin-2-onyl; or R⁶ and R⁷ togetherwith the nitrogen atom to which they are attached form a (4-CO₂R⁹)piperidino, 5-amino-3-hydroxy-1-pyrazolyl or 4-(NR¹⁰)-1-piperazinylgroup; R⁹ is H or ethyl; and R¹⁰ is H; methyl or 2-hydroxyethyl.

In another aspect, at least one of the administered PDE inhibitorcompounds is a tetracyclic cGMP specific PDE inhibitor such as thosedescribed in U.S. Pat. No. 6,143,746 and as set forth in the followingFormulae XXI-XXIII including pharmaceutically acceptable salts thereof.

More specifically, suitable compounds include those of the followingFormula XXI:

wherein in Formula XXI R⁰ represents hydrogen, halogen, or C₁₋₆ alkyl;

R¹ represents hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, haloC₁₋₆ alkyl, C₃-8 cycloalkyl, C₃-8 cycloalkyl C₁₋₃ alkyl, aryl C₁₋₃alkyl, or heteroaryl C₁₋₃ alkyl;

R² represents an optionally substituted monocyclic aromatic ringselected from benzene, thiophene, furan, and pyridine, or an optionallysubstituted bicyclic ring;

attached to the rest of the molecule via one of the benzene ring carbonatoms and wherein the fused ring A is a 5- or 6-membered ring which maybe saturated or partially or fully unsaturated and comprises carbonatoms and optionally one or two heteroatoms selected from oxygen,sulphur, and nitrogen; and

R³ represents hydrogen of C₁₋₃ alkyl, or R¹ and R³ together represent a3- or 4-membered alkyl or alkenyl chain; and pharmaceutically and saltsand solvates (e.g., hydrates) thereof.

Suitable compounds also include those of the following Formula XXII:

wherein in Formula XXII R⁰ represents hydrogen, halogen, or C₁₋₆ alkyl;

R¹ represents hydrogen, C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₃-8 cycloalkylC₁₋₃ alkyl, aryl C₁₋₃ alkyl, or heteroaryl C₁₋₃ alkyl; andR² represents an optionally substituted monocyclic aromatic ringselected from benzene, thiophene, furan, and pyridine, or an optionallysubstituted bicyclic ring

attached to the rest of the molecule via one of the benzene ring carbonatoms, and wherein the fused ring A is a 5- or 6-membered ring which canbe saturated or partially or fully unsaturated and comprises carbonatoms and optionally one or two heteroatoms selected from oxygen,sulphur, and nitrogen; and pharmaceutically acceptable salts andsolvates (e.g., hydrates) thereof.

A further subgroup of compounds of Formula XXI preferred for use in themethods of the invention, are compounds of the following Formula XXIII:

wherein in Formula XXIII:

R⁰ represents hydrogen, halogen, or C₁-C₆ alkyl;R¹ represents hydrogen or C₁₋₆ alkyl;R² represents the bicyclic ring

which can be optionally substituted by one or more groups selected fromhalogen and C₁₋₃ alkyl; and

R³ represents hydrogen or C₁₋₃ alkyl; and pharmaceutically acceptablesalts and solvates (e.g., hydrates) thereof.

In Formula XXII above, with respect to R¹, the term “aryl” as part of anaryl C₁₋₃alkyl group means phenyl or phenyl substituted by one or more(e.g., 1, 2, or 3) substituents selected from halogen, C₁-C₆ alkyl, C₁₋₆alkoxy, and methylenedioxy. The term “heteroaryl” as part of aheteroaryl C₁₋₃ alkyl group means thienyl, furyl, or pyridyl, eachoptionally substituted by one or more (e.g., 1, 2, or 3) substituentsselected from halogen, C₁₋₆ alkyl, and alkoxy. The term “C₃-8cycloalkyl” as a group or part of a C₃-8 cycloalkyl C₁₋₃ alkyl groupmeans a monocyclic ring comprising three to eight carbon atoms. Examplesof suitable cycloalkyl rings include the C₃-6 cycloalkyl ringscyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In Formula XXII above, with respect to R², optional benzene ringsubstituents are selected from one or more (e.g., 1, 2, or 3) atoms orgroups comprising halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, CO₂R^(b),halo C₁₋₆ alkyl, halo C₁₋₆ alkoxy, cyano, nitro, and NR^(a)R^(b), whereR^(a) and R^(b) are each hydrogen or C₁₋₆ alkyl, or R^(a) also canrepresent C₂₋₇ alkanoyl or C₁₋₆ alkylsulphonyl. Optional substituentsfor the remaining ring systems are selected from one or more (e.g., 1,2, or 3 atoms or groups comprising halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, andaryl C₁₋₃ alkyl as defined above. The bicyclic ring

can, for example, represent naphthalene, a heterocycle such asbenzoxazole, benzothiazole, benzisoxazole, benzimidazole, quinoline,indole, benzothiophene, benzofuran, or

wherein n is an integer 1 or 2 and X and Y each can represent CH₂, O, S,or NH.

An administered PDE inhibitor compound also may be a carbolinederivative or N-cinnamoyl derivative or (β) carbolines as described inthe U.S. Pat. Nos. 6,043,252 and 6,117,881.

Particular PDE inhibitors compounds include the following:

-   cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridyl-methyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′;6,1]-pyrido[3,4-b]indole-1,4-dione;-   cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino[2′,1′;6,1]pyrido-[3,4-b]indole-1,4-dione;-   cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methylpyrazino[2′,1′;6,1]pyrido[3,4-b]indole-1,4-dione;-   cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2′,1′;6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′;6,1]pyrido-[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′;6,1]-pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2′,1′;6,1]-pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl-pyrazino[2′,1′;6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′;6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxphenyl)-pyrazino[2′,1′;6,1]pyrido[3,4-b]indole-1,4-dione;-   (5aR,12R,14aS)-1,2,3,5,6,11,12,14a-octahydro-12-(3,4-methylenedioxyphenyl)-pyrrolo[1″,2″:4′5′]-pyrazino[2′,1′;6,1]pyrido[3,4-b]indole-5-1,4-dione;-   (6R12aR)-2,3,6,7,12,12a-hexahydro-6-(5-benzofuranyl)-2-methyl-pyrazino[2′,1′;6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R12aR)-2,3,6,7,12,12a-hexahydro-6-(5-benzofuranyl)-pyrazino[2′,1′;6,1]pyrido[3,4-b]indole-1,4-dione;-   (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(5-benzofuranyl)-3-methyl-pyrazino[2′,1′;6,1]pyrido[3,4-b]indole-1,4-dione;-   (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(5-benzofuranyl)-2,3-dimethyl-pyrazino[2′,1′,6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(5-benzofuranyl)-2-isopropyl-pyrazino[2′,    1′,6,1]pyrido[3,4-b]indole-1,4-dione;-   cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′;6,1]pyrido[3,4-b]indole-1,4-dione;-   cis-2,3,6,7,12,12-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (5aR,12R,14aS)-1,2,3,5,6,11,12,14a-Octahydro-12-(3,4-methylenedioxyphenyl)-pyrrolo[1″,2″:4′,5′]pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-5-1,4-dione;-   cis-2,3,6,7,12,12a-hexahydro-2-cyclopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-3-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;-   (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-phenylpropene-1-one;-   (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-nitrophenyl)propene-1-one;-   (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-trifluoromethylphenyl)propene-1-one;-   (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-methoxyphenyl)propene-1-one;-   (E)-1-[1-4-Methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-trifluoromethylphenyl)propene-1-one;-   (E)-N-[4-[3Oxo-3-(1-phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenyl]acetamide;-   (E)-N-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-formylphenyl)    propene-1-one;-   (E)-N-[4-[3-Oxo-3-(1-(4-nitrophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenyl]acetamide;-   (E)-1-[1-(4-Nitrophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-[1-(4-Trifluoromethoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-[1-(4-Methylphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)-propenyl]phenyl]acetamide;-   (E)-4-[3-Oxo-3-(1-phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-propenyl]benzoic    acid, methyl ester;-   (E)-1-[1-(2-Chlorophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-[1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,4-methylenedioxyphenyl)-propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-bromophenyl)-propene-1-one;-   (E)-1-[1-(4-Chlorophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-ethoxyphenyl)propene-1-one;-   (E)-4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]acetic    acid, phenyl ester;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-hydroxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-formylphenyl)propene-1-one;-   (E)-1-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)-propenyl]phenyl]-3-phenylurea;-   (E)-1-[1-3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-aminophenyl)-propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-nitrophenyl)-propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[(4-bis(methylsulfonyl)-aminophenyl]-propene-1-one;-   (E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-yl]-propenyl]benzoic    acid, methyl ester;-   (E)-N-[4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]phenyl]methanesulfonamide;-   (E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzamide];-   (E)-4-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2yl]-propenyl]benzoic    acid;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-cyanophenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-trifluoromethylphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,4-methylenedioxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-chlorophenyl)-propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-trifluoromethoxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methylphenyl)propene-1-one;-   (E)-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenyl]urea;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-hydroxymethylphenyl)propene-1-one;-   (E)-N-Benzyl-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-beta-carbolin-2-yl)propenyl]benzamide;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2,4-dichlorophenyl)propene-1-one;-   (E)-1-[1-3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-methoxy-4-hydroxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-hydroxy-4-methoxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-fluorophenyl)-propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-indan-5-yl-1-propene-1-one;-   (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzoyl]benzenesulfonamide;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,4-dichlorophenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,4-dimethoxyphenol)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,4-dihydroxyphenyl)propene-1-one;-   (E)-N-Methyl-N-[4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenyl]acetamide;-   (E)-2,2-Dimethyl-N-[4-[3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenyl]propionamide;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,5-dimethoxyphenyl)propene-1-one;-   (E)-(N)-{4-[3-[1-(3,4-Methylenedioxyphenyl)-6-fluoro-1,3,4,9-tetrahydro-beta-carbolin-2-yl]-3-oxopropenyl]-phenyl}-acetamide;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,4,5-trimethoxyphenyl)propene-1-one;-   (E)-N-[4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenyl]isobutyramide;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-6-fluoro-1,3,4,9-tetrahydro-β-2-yl]-3-phenylpropene-1-one;-   (E)-N-(2-Methoxyethyl)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-hydroxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-methoxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[4-(2-(methylaminoethoxy)phenyl]propene-1-one;-   (E)-N-(2-Morpholin-4-ylethyl)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide;-   (E)-1-[1-(3,4′-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[4-(1H-tetrazol-5-yl)phenyl]propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-aminophenyl)propene-1-one;-   (E)-N-Cyclohexyl-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide;-   (E)-N-(Tetrahydrofuran-2-ylmethyl)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-cyanophenyl)propene-1-one;-   (E)-N-(4-Piperidine-4-carboxylic acid, ethyl    ester)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide;-   (E)-N-(4-Piperidine-4-carboxylic    acid)-4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide;-   (E)-3-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-propenyl]benzoic    acid;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-(4-methylpiperazine-1-carbonyl)-phenyl)propene-1-one;-   (E)-N-(2-piperazine-1-ylethyl)-3-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide;-   (E)-4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)-propenyl]acetic    acid ethyl ester;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-tetrazolophenyl)propene-1-one;-   (E)-2-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzoic    acid, methyl ester;-   (E)-3-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzoic    acid, methyl ester;-   (E)-1-(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)-propenyl]phenyl)piperidine-4-carboxylic    acid, ethyl ester;-   (E)-N-(1-Ethylpyrrolidin-2-yl-methyl)-3-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-2-yl)propenyl]benzamide;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-(2-dimethylaminoethoxy)phenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,5-diterbutyl-4-hydroxyphenyl)propene-1-one;-   (E)-3-[3-Oxo-3-[1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahydro-β-2-yl]propenyl]benzoic    acid, methyl ester;-   (E)-2-[3-Oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-2-yl]propenyl]benzoic    acid;-   (E)-(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenoxy)acetic    acid, ethyl ester;-   (E)-(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)-propenyl]phenyl)acetic    acid;-   (E)-(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenoxy)acetic    acid;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitro-4-chlorophenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(5-nitro-2-chlorophenyl)propene-1-one;-   (E)-3-Chloro-4-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-beta.-carbolin-2-yl]propenyl]benzoic    acid, methyl ester,-   (E)-(4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzyloxy)acetic    acid;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(5-amino-2-chlorophenyl)propene-1-one;-   (E)-3-Chloro-4-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-beta-carbolin-2-yl]propenyl]benzoic    acid;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3,5-dibromo-4-hydroxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one;-   (E)-2-Chloro-5-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-beta-carbolin-2-yl]propenyl]benzoic    acid, methyl ester;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(2-diisopropylaminoethoxy)phenyl)propene-1-one;-   (E)-2-Chloro-5-[3-oxo-3-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-beta-carbolin-2-yl]propenyl]benzoic    acid;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-hydroxy-4-nitro-phenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2]-3-(3,5-dimethyl-4-hydroxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-(2-dimethylaminoethoxy)-4-nitro-phenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-(2-dimethylaminoethoxy)-4-amino-phenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitro-4-hydroxy-5-methoxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-chlorophenyl)propene-1-one;-   (E)-1-[1-(4-Methoxy-phenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2,6-dichlorophenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methylaminomethylphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-methylphenyl)propene-1-one;-   (E)-N-Methyl-(4-[3-oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-beta-carbolin-2-yl)propenyl]benzenesulfonamide;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-hydroxy-4-acetylphenyl)propene-1-one;-   (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-hydroxyphenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitro-2-piperidin-1-ylphenyl)propene-1-one;-   (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-[1-(4-Isopropylphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one;-   (E)-1-[1-(2,3-Diydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one;-   (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-(S)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one;-   (E)-1-[1-(4-Methylphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-chloro-5-nitrophenyl)propene-1-one;-   (E)-N-(Tetrahydrofuran-2-ylmethyl)-3-[3-oxo-3-(1-(3,4-methylenedioxy)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]benzamide;-   (E)-1-[1-(Indan-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-acetylphenyl)propene-1-one;-   (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one;-   (E)-4-[3-Oxo-3-[1-(4-methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzoic    acid, methyl ester;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methyl-3,4-dihydro-2H-benzo[1,4]-oxazin-6-yl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-hydroxy-5-nitrophenyl)propene-1-one;-   (E)-4-[3-Oxo-3-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzoic    acid, methyl ester;-   (E)-4-[3-Oxo-3-[1<4-methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzoic    acid;-   (E)-4-[3-Oxo-3-[1-(2,3-dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzoic    acid;-   (E)-1-[1-(Benzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-3-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)-propenyl]phenyl)trifluoromethanesulfonic    acid, phenyl ester;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[4-(2-hydroxyethoxy)phenyl]propene-1-one;-   (E)-1-[1-(Benzofuran-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-dimethylaminophenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-piperidin-1-ylphenyl)propene-1-one;-   (E)-4-[3-Oxo-3-[1-(benzofuran-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl]-propenyl]-benzoic    acid, methyl ester;-   (E)-4-[3-(1-Benzofuran-5-yl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-oxo-propenyl]-benzoic    acid;-   (E)-4-[3-Oxo-3-(1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)propenyl]phenyl)trifluoromethanesulfonic    acid, phenyl ester;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(2-(2-dimethylaminoethoxy)phenyl)propene-1-one;-   (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one;-   (E)-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[4-pyrrolidin-1-ylphenyl]propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[4-imidazol-1-ylphenyl]propene-1-one;-   (E)-4-[3-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-tetrahydro-β-carbolin-2-yl]3-Oxo-propenyl]benzoic    acid, methyl ester;-   (E)-1-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one;-   (E)-1-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one;-   (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one;-   (E)-4-[3-[1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-oxopropenyl]benzoic    acid;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-(S)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylaminoethoxy)phenyl)propene-1-one;-   (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one;-   (E)-(S)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-phenylpropene-1-one;-   (E)-(S)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-nitrophenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(1-(S)-methylpyrrolidin-2-yl-methoxy)phenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-hydroxyphenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylamino-1-methylethoxy)phenyl)propene-1-one;-   (E)-1-(1-Phenyl-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-(4-methylpyperazin-1-yl)-phenyl)propene-1-one;-   (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(1-(S)-methylpyrrolidin-2-yl-methoxy)phenyl)propene-1-one;-   (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylamino-1-methylethoxy)phenyl)propene-1-one;-   (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one;-   (E)-4-[3-Oxo-3-[1-(3,4-fluorophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzoic    acid, methyl ester;-   (E)-(R)-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]3-(4-(2-diethylaminoethoxy)phenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-dimethylaminopropoxy)phenyl)propene-1-one;-   (E)-4-[3-Oxo-3-[1-(3,4-difluorophenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]propenyl]benzoic    acid;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one;-   (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-aminophenyl)propene-1-one;-   (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-pyrrolidin-1-ylethoxy)phenyl)propene-1-one;-   (E)-(R)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(4-(2-diethylaminoethoxy)phenylpropene-1-one;-   (E)-1-[1-(3-Fluoro-4-methoxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)]-3-(3-nitrophenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-trifluoromethylphenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(3-trifluoromethylphenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(2-morpholin-4-ylethoxy)phenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(2-(ethylmethylamino)ethoxy)phenyl)propene-1-one;-   (E)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(3-(dimethylamino)propenyl)phenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(3-dimethylamino-2-hydroxypropoxy)phenyl)propene-1-one;-   (E)-(R)-1-(1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-formylphenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-propylaminoethyl)phenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[4-(2-dimethylaminoethylamino)phenylpropene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(2-aminoethoxy)phenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-hydroxyphenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(4-methylpiperazin-1-yl)phenylpropene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methylaminomethyl)phenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-isopropylaminomethyl)phenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-dimethylaminomethyl)phenyl)propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]3-[4-(3-dimethylaminopropoxy)phenyl]propene-1-one;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-(2-piperidin-1-ylethoxy)phenyl)propene-1-one;-   (E)-1-[1-(3,4-Methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl)-3-(4-(2-piperidin-1-ylethoxy)phenyl]propene-1-one;-   (E)-(R)-[2-(4-{3-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-oxopropenyl}-phenoxy)ethyl]methylcarbamic    acid, tertbutyl ester;-   (E)-(R)-1-[1-(2,3-Dihydrobenzofuran-5-yl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-[4-(2,3-methylaminoethoxy)phenyl]propene-1-one;    and pharmaceutically acceptable salts and solvates (e.g., hydrates)    of such compounds.

Additional preferred PDE inhibitor compounds for use in accordance withthe invention may be identified by simple testing, such as in byexhibiting an ID₅₀ of less than about 10 mM, preferably less than about1 mM in an in vitro assay for determining PDE or PDE-5 inhibitory actionas disclosed in U.S. Pat. No. 6,100,270; WO-A-93/06104; WO-A-93/07149;WO-A-93/12095; and WO-A-94/00453.

As indicated above, the present invention includes methods for treatingor preventing prostalandin mediated or associated diseases or disorders.

Preferred therapeutic methods of the invention include inhibitingundesired smooth muscle contraction, including undesiredprostanoid-induced smooth muscle contraction. Methods of die inventioninclude treatment of a patient suffering from or susceptible todysmenorrhea, premature labor, asthma and other conditions that can berelieved by bronchodilation, inflammation, hypertension, undesiredblood-clotting (e.g. to reduce or prevent thromboses) and otherundesired platelet activities, preeclampsia and/or eclampsia andeosinophil-related disorders (eosinophil disorders).

Treatment and/or prevention of undesired blood clotting may includetreatment and prophylaxis of venous thrombosis and pulmonary embolism,arterial thrombosis e.g. myocardial ischemia, myocardial infarction,unstable angina, stroke associated with thrombosis, and peripheralarterial thrombosis. Pyrrolidine compounds of the invention also may beuseful for anticoagulation involving artificial organs, cardiac valves,medical implementation (e.g. an indwelling device such as a catheter,stent, etc.) and the like.

The invention also includes methods for treatment of infertility, whichgenerally comprise administration of one or more pyrrolidine compoundsof the invention to a mammal, particularly a primate such as a human,suffering from or suspected of suffering from infertility. See the MerckManual, vol. 2, pages 12-17 (16^(th) ed.) for identification of patientssuffering from or suspected of suffering from infertility, which in thecase of humans, can include failure to conceive within one year ofunprotected intercourse.

The treatment methods of the invention may be particularly beneficialfor female mammals suffering from an ovulatory disorder. Additionally,compounds of the invention can be administered to females undergoingassisted reproductive treatments such as in-vitro fertilization, e.g. tostimulate follicular development and maturation, as well as implantationprocedures. In particular, treatment methods of the invention may beused in conjunction with in vitro fertilization technology to enhancesurvival and/or fertilization of a mammalian egg such as in IVF setting.

Treatment methods of the invention also may be employed for control ofcervical ripening in late pregnancy (e.g. in humans, late pregnancywould be third trimester, particularly week 30 onward).

Therapeutic methods of the invention also include treatment of glaucoma,inhibition or prevention of bone loss such as to treat osteoporosis, andfor promoting bone formation (e.g. to use as a therapy in a bonefracture) and other bone diseases such as Paget's disease.

Compounds of the invention also will be useful to treat sexualdysfunction, including male erectile dysfunction.

The therapeutic methods of the invention generally compriseadministration of an effective amount of one or more pyrrolidinecompounds of the invention to a subject including a mammal, such as aprimate, especially a human, in need of such treatment.

Typical candidates for treatment in accordance with the methods of theinvention persons suffering from or suspected of suffering from any ofthe above disorders or diseases, such as a female susceptible orsuffering from preterm labor, or a subject suffering from or susceptibleto dysmenorrhea or undesired bone loss.

The treatment methods of the invention also will be useful for treatmentof mammals other than humans, including for veterinary applications suchas to treat horses and livestock e.g. cattle, sheep, cows, goats, swineand the like, and pets such as dogs and cats. Methods of the inventionto treat premature labor will be particularly useful for such veterinaryapplications. Therapeutic methods of the invention also will be usefulfor treatment of infertility in such veterinary applications.

For diagnostic or research applications, a wide variety of mammals willbe suitable subjects including rodents (e.g. mice, rats, hamsters),rabbits, primates and swine such as inbred pigs and the like.Additionally, for in vitro applications, such as in vitro diagnostic andresearch applications, body fluids (e.g., blood, plasma, serum, cellularinterstitial fluid, saliva, feces and urine) and cell and tissue samplesof the above subjects will be suitable for use.

In addition to coordinated administration with a PDE inhibitor compoundas discussed above, pyrrolidine compounds of the invention may beadministered as a “cocktail” formulation with other therapeutics, i.e.coordinated administration of one or more compounds of the inventiontogether with one or more other active therapeutics, particularly one ormore other known fertility agents. For instance, one or more compoundsof the invention may be administered in coordination with a regime of apain relief agent, an anti-inflammatory agent, or an anti-coagulant,depending on the indication being treated. Suitable anti-coagulants forsuch coordinated drug therapies include e.g. warfarin, heparin, hirudinor hirulog or an antiplatelet such as ReoPro.

For treatment of fertility disorders, one or more compounds of theinvention may be suitably administered in coordination with knownfertility agents such as Follicle Stimulating and/or Leutinizing Hormonesuch as Gonal-F, Metrodin HP or Pergonal.

Pyrrolidine compounds of the invention either as the sole activetherapeutic or in a coordinated regime such as together with one or morePDE inhibitor compounds can be administered by a variety of routes, suchas orally or by injection, e.g., intramuscular, intraperitoneal,subcutaneous or intravenous injection, or topically such astransdermally, vaginally and the like. Pyrrolidine compounds of theinvention may be suitably administered to a subject in the protonatedand water-soluble form, e.g., as a pharmaceutically acceptable salt ofan organic or inorganic acid, e.g., hydrochloride, sulfate,hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate,mesylate, etc. If the compound has an acidic group, e.g. a carboxygroup, base addition salts may be prepared. Lists of additional suitablesalts may be found, e.g. in Part 5 of Remington's PharmaceuticalSciences, 20th Edition, 2000, Marck Publishing Company, Easton, Pa.

Pyrrolidine compounds of the invention can be employed, either alone orin combination with one or more other therapeutic agents as discussedabove, as a pharmaceutical composition in mixture with conventionalexcipient, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for oral, parenteral, enteral or topicalapplication which do not deleteriously react with the active compoundsand are not deleterious to the recipient thereof. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt solutions, alcohol, vegetable oils, polyethylene glycols,gelatin, lactose, amylose, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like which do not deleteriously react withthe active compounds.

Pharmaceutical compositions of the invention include a pyrrolidinecompound of the invention packaged together with instructions (written)for therapeutic use of the compound to treat e.g. premature labor,dysmenorrhea or asthma, or other disorder as disclosed herein, such as adisease or disorder associated with or mediated by prostaglandin.

For oral administration, pharmaceutical compositions containing one ormore substituted pyrrolidine compounds of the invention may beformulated as e.g. tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, syrups, elixers and the like. Typically suitable are tablets,dragees or capsules having talc and/or carbohydrate carrier binder orthe like, the carrier preferably being lactose and/or corn starch and/orpotato starch. A syrup, elixir or the like can be used wherein asweetened vehicle is employed. Sustained release compositions can beformulated including those wherein the active component is protectedwith differentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

For parenteral application, e.g., sub-cutaneous, intraperitoneal orintramuscular, particularly suitable are solutions, preferably oily oraqueous solutions as well as suspensions, emulsions, or implants,including suppositories. Ampules are convenient unit dosages.

It will be appreciated that the actual preferred amounts of activecompounds used in a given therapy will vary according to the specificcompound being utilized, the particular compositions formulated, themode of application, the particular site of administration, etc. Optimaladministration rates for a given protocol of administration can bereadily ascertained by those skilled in the art using conventionaldosage determination tests conducted with regard to the foregoingguidelines. See also Remington's Pharmaceutical Sciences, supra. Ingeneral, a suitable effective dose of one or more pyrrolidine compoundsof the invention, particularly when using the more potent compound(s) ofthe invention, will be in the range of from 0.01 to 100 milligrams perkilogram of bodyweight of recipient per day, preferably in the range offrom 0.01 to 20 milligrams per kilogram bodyweight of recipient per day,more preferably in the range of 0.05 to 4 milligrams per kilogrambodyweight of recipient per day. The desired dose is suitablyadministered once daily, or several sub-doses, e.g. 2 to 4 sub-doses,are administered at appropriate intervals through the day, or otherappropriate schedule. Such sub-doses may be administered as unit dosageforms, e.g., containing from 0.05 to 10 milligrams of compound(s) of theinvention, per unit dosage.

The entire text of all documents cited herein are incorporated byreference herein. The following non-limiting examples are illustrativeof the invention. In the examples below, “rac.” refers to a racemate orracemic mixture of the specified compound.

EXAMPLES 1-21 Synthesis of Compounds of the Invention

The compounds of Examples 1 to 21 are preferred embodiments of theinvention:

Example 1 Synthesis of(5Z)7-[(2R,3R)-3-Chloro-1-(4-hydroxynonyl)-pyrrolidin-2-yl]-hept-5-enoicacid (Scheme 2, Steps A-B and D-F)

Intermediate 1.1:methyl(3-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-yl)acetate.

To a methanolic solution (50 mL) of3-(tert-butyl-dimethyl-silanyloxy)-2-methoxycarbonylmethyl-pyrrolidin-1-carboxylicacid benzyl ester (obtained from 3-aminopropanal according to theprocedure of Macdonald et al: J. Med. Chem. 1998, 41(21), 3919-3922))(10.0 g. 0.025 mol) was added Pd/C (1.0 g). The mixture was stirredunder H₂ atmosphere (1 atm) for 4 h, then filtered through celite andconcentrated under reduced pressure to afford the desired intermediate(6.0 g, 90%) as a colorless oil used in the next step without furtherpurification. ¹H NMR (CDCl₃) δ (mixture of diastereoisomers) 0.05 (s,6H), 0.87 (s, 9H), 1.65-1.82 (m, 1H), 1.95-2.05 (m, 1H), 2.3-2.7 (m,2H), 2.95-3.4 (m, 2H), 3.67-3.68 (2s, 3H), 3.90-4.31 (m, 1H); MS (m/z)274.2 (M+1).

Intermediate 1.2:tert-butyl3-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate.

To a solution of intermediate 1.1 (6.0 g, 0.022 mol) in DCM (100 mL)were added di-tert-butyl dicarbonate (3.7 mL, 0.026 mol), Et₃N (3.7 mL,0.026 mol), and DMAP (0.6 g). The resulting solution was stirred at RTfor 18 h then was washed with HCl 1.0M (2×100 mL) and brine (100 mL),dried over sodium sulfate and concentrated in vacuo to afford thedesired intermediate (8.0 g, 97%) as a pale yellow oil used in the nextstep without further purification. R_(f) 0.6 (EtOAc/hexane 1/4); ¹H NMR(CDCl₃) δ (mixture of diastereoisomers) 0.04-0.06 (2s, 6H), 0.88-0.90(2s, 9H), 1.42-1.45 (2s, 9H), 1.70-2.20 (m, 2H), 2.55-2.90 (m, 2H),3.30-3.55 (m, 2H), 3.60-3.70 (2s, 3H), 3.8-4.0 (m, 1H).

Intermediate 1.3 and 1.4:tert-butyl3-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-hydroxyethyl)pyrrolidin-1-carboxylate.

To a solution of intermediate 1.2 (7.5 g, 0.02 mol) in dry benzene (150mL) was added dropwise a solution of Red-Al (6.3 mL, 65+wt % solution intoluene, 0.022 mol). This solution was stirred at reflux for 1 h thencooled to RT and quenched with a saturated solution of Rochelle salt.The mixture was extracted with EtOAc (2×150 mL) and the collectedorganic phase was washed with brine (200 mL), dried and concentrated invacuo. The crude mixture of diastereoisomers was purified by silica gelflash column chromatography using EtOAc/hexane as eluent to afford thedesired intermediates.

Intermediate 1.3 (cis isomer): R_(f) 0.30 (EtOAc/hexane 1/4); ¹H NMR(CDCl₃) δ 0.06 (s, 6H), 0.88 (s, 9H), 1.2-1.4 (m, 2H), 1.45 (s, 9H),1.90-2.10 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.72 (m, 2H), 4.00-4.10 (m,1H), 4.25-4.40 (m, 2H); MS (m/z): 346 (M+1).Intermediate 1.4 (trans isomer): R_(f) 0.25 (EtOAc/hexane 1/4); ¹H NMR(CDCl₃) δ 0.05 (s, 6H), 0.85 (s, 9H), 1.1-1.2 (m, 1H), 1.45 (s, 9H),1.70-2.00 (m, 2H), 3.30-3.70 (m, 5H), 3.85-4.02 (m, 2H), 4.53 (dd, J=5.5and 9.5 Hz, 1H); MS (m/z): 346 (M+1).

Intermediate 1.5:tert-butyl(2R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-[(2Z)-7-methoxy-7-oxohept-2-enyl]pyrrolidine-1-carboxylate.

Step A (Swern Oxidation):

A DCM solution of oxalyl chloride (5.3 mL, 2.0 M, 10.55 mmol) wasdiluted with dry DCM (50 mL) and cooled to −70° C. then a solution ofDMSO (0.92 mL, 13 mmol) in DCM (10 mL) was added dropwise. After 15 min.to this solution was added dropwise a solution of intermediate 1.3 (2.8g, 8.1 mmol) in DCM (20 mL). The resulting solution was stirred at −78°C. for 45 min. then Et₃N (5.6 mL, 40.6 mmol) was added and the solutionwarmed to RT. After 15 min. the solution was diluted with DCM (100 mL)and washed with a saturated solution of NH₄Cl (2×100 mL), brine (100mL), dried over sodium sulfate and concentrated in vacuo to afford thealdehyde intermediate (2.75 g, 97%) used in the next step withoutfurther purification. R_(f) 0.40 (EtOAc/hexane 1/4); ¹H NMR (CDCl₃) δ0.04-0.07 (2s, 6H), 0.86 (s, 9H), 1.43 (s, 9H), 1.70-2.05 (m, 2H),2.50-2.85 (m, 2H), 3.30-3.45 (m, 2H), 4.20-4.30 (m, 1H), 4.39 (dd, J=62and 12.5 Hz, 1H); MS (m/z): 344 (M+1).

Step B (Wittig Reaction):

A suspension of (4-carboxybutyl)triphenylphosphonium bromide (5.1 g,11.6 mmol) in THF (40 mL) was cooled to 0° C. and KO^(t)Bu was addedportionwise. After 15 min. was added a solution of the aldehyde (2.75 g,8.1 mmol) in THF (10 mL). The resulting mixture was stirred at RT for 18h then was diluted EtOAc (150 mL) and washed with HCl 1M solution (100mL) and brine. The organic phase was dried over sodium sulfate andconcentrated in vacuo to afford the crude acid used directly in the nextstep.

Step C (Esterification Reaction):

To a solution of the crude acid in DCM (30 mL) and MeOH (7 mL) was addeddropwise a solution of trimethylsylildiazomethane (50 mL, 2 M solutionin hexane, 12 mmol). The resulting solution was stirred at RT for 18 hthen was concentrated under reduced pressure. The crude residue wassubjected to flash chromatography and was eluted with EtOAc/hexane toafford the desired intermediate (3.1 g, 88%) as a colorless oil. R_(f)0.50 (EtOAc/hexane 1/4); ¹H NMR (CDCl₃) δ 0.07 (s, 6H), 0.88 (s, 9H),1.44 (s, 9H), 1.60-1.70 (m, 2H), 1.80-2.15 (m, 4H), 2.20-2.45 (m, 4H),3.25-3.40 (m, 2H), 3.65 (s, 3H), 3.66-3.90 (m, 1H), 4.25-4.33 (m, 1H),5.30-5.40 (m, 1H), 5.43-5.58 (m, 1H).

Intermediate 1.6: rac.tert-butyl(2R)-3-hydroxy-2-[(2Z)-7-methoxy-7-oxohept-2-enyl]pyrrolidine-1-carboxylate.

To a solution of intermediate 1.5 (3.0 g, 6.8 mmol) in THF (20 mL) wasadded dropwise a solution of TBAF (7.5 mL, 1.0 M, 7.5 mmol) in THF. Theclear solution was stirred at RT for 2 h then was concentrated underreduced pressure. The residue was diluted with EtOAc (100 mL), Washedwith water (100 mL), brine (100 mL), dried over sodium sulfate andconcentrated in vacuo to afford the alcohol intermediate (1.95 g, 88%)used in the next step without further purification. R_(f) 0.40(EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ 1.45 (s, 9H), 1.65-1.75 (m, 2H),1.80-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.26-2.45 (m, 4H), 3.32-3.50 (m,3H), 3.66 (s, 3H), 3.75-3.86 (m, 1H), 4.32-4.42 (m, 1H), 5.35-5.55 (m,2H).

Intermediate 1.7: rac.tert-butyl(2R)-2-[(2Z)-7-methoxy-7-oxohept-2-enyl]-3-{[(4-methylphenyl)sulfonyl]oxy}pyrrolidine-1-carboxylate.

To a solution of intermediate 1.6 (0.5 g, 1.53 mmol) in pyridine (5 mL)was added tosyl chloride. The solution was stirred at RT for 10 h thenat 50° C. for an additional 4 h. The reaction mixture was concentratedin vacuo, diluted with EtOAc (100 mL) and washed with HCl 1.0 M (100mL), brine (100 mL), dried over sodium sulfate and concentrated invacuo. The crude residue was subjected to flash chromatography and waseluted with EtOAc/hexane to afford the desired intermediate (0.51 g,70%) as colorless oil. R_(f) 0.3 (EtOAc/hexane 1/4); ¹H NMR (CDCl₃) δ1.20-1.30 (m, 1H), 1.41 (s, 9H), 1.60-1.75 (m, 2H), 1.90-2.15 (m, 4H),2.20-2.50 (m, 3H), 2.45 (s, 3H), 3.20-3.45 (m, 2H), 3.64 (s, 3H),3.85-3.95 (m, 1H), 4.91 (q, J=6.6 Hz, 1H), 5.30-5.45 (m, 2H), 7.32 (d,J=8.1 Hz, 2H)), 7.78 (d, J=8.1 Hz, 2H).

Intermediate 1.8: rac.tert-butyl(2R)-3-chloro-2-[(2Z)-7-methoxy-7-oxohept-2-enyl]pyrrolidine-1-carboxylate.

To a solution of intermediate 1.7 (0.9 g, 1.80 mmol) in dry toluene (60mL) was added tetrabutyl ammonium chloride (5.0 g, 18.0 mmol). Thereaction mixture was stirred at 55° C. for 48 h then was diluted withwater and extracted with EtOAc (2×100 mL). The collected organic phasewas washed with water (2×100 mL), saturate solution of NaHCO₃ (100 mL),and brine (100 mL). The organic solution was dried over sodium sulfateand concentrated in vacuo to afford the desired intermediate (0.6 g,96%) as a colorless oil. R_(f) 0.50 (EtOAc/hexane 1/4); ¹H NMR (CDCl₃) δ1.46 (s, 9H), 1.60-1.75 (m, 2H), 2.02-2.16 (m, 4H), 2.25-2.55 (m, 4H),3.38-3.70 (m, 2H), 3.66 (s, 3H), 3.87-4.08 (m, 1H), 4.15-4.25 (m, 1H),5.30-5.55 (m, 2H).

Intermediate 1.9: rac.Methyl(5Z)-7-[(2R,3R)-3-chloropyrrolidin-2-yl]hept-5-enoate.

Intermediate 1.8 (0.30 g, 0.87 mmol) was treated with a solution of HClin dioxane (6 mL, 4M solution). The resulting solution was stirred at 0°C. for 2 h then was concentrated under reduced pressure. The cruderesidue was diluted with a saturated solution of NaHCO₃ (50 mL) andextracted with EtOAc (3×40 mL). The collected organic phase was washedwith brine (100 mL), dried over sodium sulfate and concentrated underreduced pressure to afford the amine intermediate (0.24 g, 95%) used inthe next step without further purification. MS (m/z): 246 (M+1).

Intermediate 1.10: tert-Butyl(dimethyl)[(1-pentylprop-2-ynyl)oxy]silane.

To a solution of (R)-1-octyn-3-ol (5.0 g, 0.039 mol) in DMF (50 mL) wereadded tert-butyldimethylsylil chloride (7.16 g, 0.0475 mol) andimidazole (3.2 g, 0.0475 mol). The resulting solution was stirred at RTfor 18 h then diluted with ether (200 mL) and washed with water (2×200mL), saturated solution of NH₄Cl (200 mL), and brine (200 mL). Theorganic solution was dried over sodium sulfate and concentrated in vacuoto afford the desired compound (9.0 g, 95%) as a colorless oil used inthe next step without further purification. R_(f) 0.9 (EtOAc/hexane1/9); ¹H NMR (CDCl₃) δ 0.09 (s, 3H), 0.12 (s, 3H), 0.89 (s, 9H),0.85-1.00 (t, 3H), 1.20-1.70 (m, 8H), 2.35 (s, 1H), 4.30-4.35 (m, 1H).

Intermediate 1.11: (4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}non-2-yn-1-ol.

To a solution of intermediate 1.10 (0.50 g, 2.08 mmol) in dry THF (15mL) cooled at −70° C. was added dropwise a solution of n-BuLi in hexane(1.36 mL, 1.6 M, 2.18 mmol). The resulting solution was stirred at −70°C. for 10 minutes then para-formaldehyde (0.16 g, 5.46 mmol) was added.The resulting mixture was stirred at RT for 4 h then was diluted withEtOAc (100 mL) and washed with a saturated solution of NH₄Cl (100 mL),brine (100 mL), dried and concentrated in vacuo. The crude residue waspurified by flash column chromatography (EtOAc/hexane) to afford thetitle compound (0.42 g, 75%) as a colorless oil. R_(f) 0.3 (EtOAc/hexane1/9); ¹H NMR (CDCl₃) δ 0.09 (s, 3H), 0.11 (s, 3H), 0.89 (s, 9H),0.85-0.90 (t, 3H), 1.20-1.70 (m, 8H), 4.27 (s, 2H), 4.30-4.40 (m, 1H).

Intermediate 1.12: (4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}nonan-1-ol.

A heterogeneous mixture of intermediate 1.11 (1.0 g, 5.3 mmol) and 10%Pd/C (catalytic amount) in EtOAc (20 mL) was stirred in an atmosphere ofhydrogen for 3 h. The solvent was filtered via celite, concentrated invacuo to give a glassy residue of two products which were separated byflash chromatography (EtOAc-hexane 1/9) gave the saturated alcohol 1.12(0.79 g, 77%): R_(f) 0.10 (EtOAc/hexane 1/9), MS (m/z) 276 (M+1) and thecorrespondent aldehyde 1.13 (0.24 g 23%): R_(f)=0.47 (EtOAc/hexane 1/9),MS (m/z) 273 (M+1).

Intermediate 1.13: (4R)-4-{[tert-Butyl(dimethyl)silyl]oxy}nonanal.

A solution of oxalyl chloride in DCM (1.85 mL, 2.0 M, 3.70 mmol,) wasdiluted with dry DCM (20 mL) and cooled to −70° C. and a solution ofDMSO (0.32 mL, 4.55 mmol) in DCM (5.0 mL) was added dropwise. After 15min., to the above solution was added dropwise a solution ofintermediate 1.12 (0.78 g, 2.84 mmol) in DCM (10 mL). The resultingsolution was stirred at −78° C. for 45 min. then Et₃N (2.0 mL, 14.23mmol) was added and the solution was warmed to RT. After 15 min. thesolution was diluted with DCM (50 mL) and washed with a saturatedsolution of NH₄Cl (2×50 mL), brine (50 mL), dried over sodium sulfateand concentrated in vacuo to afford the aldehyde intermediate (0.80 g,98%) used in the next step without further purification. R_(f) 0.50(EtOAc/hexane 1/9).

Intermediate 1.14: roc.Methyl(5Z)-7-[(2R,3R)-1-(4-{[tert-butyl(dimethyl)-silyl]oxy}nonyl)-3-chloropyrrolidin-2-yl]hept-5-enoate.

To a solution of intermediate 1.9 (0.15 g, 0.61 mmol) and intermediate1.13 (0.20 g, 0.74 mmol) in MeOH (10 mL) was added a solution of NaCNBH₃in THF (1.2 mL, 1.0 M, 1.20 mmol). The resulting solution was stirred atRT for 18 h then was concentrated in vacuo, diluted with EtOAc (50 mL)and washed with a saturated solution of NaHCO₃ (50 mL), and brine (50mL). The organic solution was dried over sodium sulfate and concentratedin vacuo. The crude residue was purified by silica gel flash columnchromatography using EtOAc/hexane as eluent to afford the desiredintermediate (0.29 g, 96%) as a colorless oil. R_(f) 0.75 (EtOAc/hexane1/4); MS (m/z): 503 (M+1).

Intermediates 1.15 and 1.16:methyl(5Z)-7-[3-chloro-1-(4-hydroxynonyl)-pyrrolidin-2-yl]hept-5-enoate.

To a solution of intermediate 1.14 (1.20 g, 1.22 mmol) in dioxane (40mL) was added a solution of HCl in dioxane (10 mL, 4.0 M). The solutionwas stirred at RT for 2 h then was concentrated under reduced pressure.The crude residue was diluted with a saturated solution of NaHCO₃ (20mL) and extracted with EtOAc (3×30 mL). The collected organic phase waswashed with brine, dried, and concentrated under reduced pressure.Silica gel column chromatography eluted with EtOAc/hexane allowed theseparation of the two diastereoisomers intermediate. Intermediate 1.15(first isomer, 240 mg): R_(f) 0.5 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ0.80-0.95 (m, 3H), 1.20-1.80 (m, 15H), 1.95-2.52 (m, 10H), 2.65-2.72 (m,1H), 2.75-2.85 (m, 1H), 3.15-3.27 (m, 1H), 3.40-3.52 (m, 1H), 3.66 (s,3H), 3.95-4.05 (m, 1H), 5.40-5.55 (m, 2H). Intermediate 1.16 (secondisomer, 220 mg): R_(f) 0.45 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ0.80-0.95 (m, 3H), 1.20-1.80 (m, 15H), 1.95-2.60 (m, 10H), 2.65-2.85 (m,2H), 3.10-3.25 (m, 1H), 3.40-3.52 (m, 1H), 3.65 (s, 3H), 3.95-4.05 (m,1H), 5.40-5.55 (m, 2H).

The title compound,(5Z)7-[(2R,3R)-3-chloro-1-(4-hydroxynonyl)-pyrrolidin-2-yl]-hept-5-enoicacid, was then prepared as follows. To a solution of intermediate 1.16(0.22 g, 0.56 mmol) in MeOH (3.4 mL) and THF (3.4 mL) was added asolution of NaOH in water (1.13 mL, 1.0 M, 1.134 mmol). The resultingsolution was stirred at RT for 20 h, then was concentrated under reducedpressure. The crude residue was diluted with water (10 mL) and washedwith ether (2×10 mL). The aqueous solution was lyophilized to obtain thedesired compound (240 mg) as a pale yellow solid. MS (m/z) 374 (M+1).

Example 2a and 2b Preparation of rac.(5Z)-7-(-3-chloro-1-{4-[1-(cyclopropyl-methyl)cyclobutyl]-4-hydroxybutyl}pyrrolidin-2-yl)hept-5-enoicacid (Scheme 2, Steps A-B and D-F)

Intermediate 2.1: 1-(cyclopropylmethyl)cyclobutanecarboxylic acid

To a solution of LDA (100 ml, 2.0 M THF solution) in THF (100 ml) wasadded dropwise over a period of 20 minutes at 0° C., a solution ofcyclobutane carboxylic acid (10 g, 0.1 mol) in THF (15 ml). Theresulting mixture was stirred at RT for 2 h then bromoethyl cyclopropane(15 g, 0.11 mol) was added dropwise and the mixture was stirred at RTovernight. To the reaction mixture was added 2N HCl and the mixture wasextracted with EtOAc. The organic layer was washed with water and brineto afford the title compound as light yellow oil (19.2 g), which wasused in the next step without purification.

Intermediate 2.2: [1-(cyclopropylmethyl)cyclobutyl]methanol

To a solution of lithium aluminum hydride (150 ml, 1.0 M THF solution)was added dropwise a solution of intermediate 2.1 (19 g) in THF (25 ml)and the mixture was refluxed for 0.5 hours. The reaction mixture wascooled with ice and quenched with the slowly addition of water. Themixture was filtered through celite and the filtrate was concentrated.The crude residue was purified by flash column chromatography(EtOAc/hexane) to afford the title compound (8.83 g) as a colorless oil.R_(f) 0.40 (EtOAc/hexane 1/5) ¹H NMR (CDCl₃) δ 0.05 (m, 2H), 0.42 (m,2H), 0.62 (m, 1H), 1.42 (d, J=6.96 Hz, 2H), 1.78-1.84 (m, 6H), 3.64 (s,2H).

Intermediate2.3:tert-butyl({1-[1-(cyclopropylmethyl)cyclobutyl]prop-2-ynyl}-oxy)dimethylsilane.

To a solution of oxalyl chloride (47 ml, 2.0 M solution in DCM) inmethylene chloride (100 ml) at −78° C. was added dropwise a solution ofDMSO (13.4 ml) in methylene chloride (12 ml) and the mixture was stirredat that temperature for 30 minutes. To this solution was added dropwisea solution of intermediate 23 (8.8 g) in methylene chloride (12 ml) andthe temperature was raised to −40° C. over a period of 30 minutes. Tothis solution was added Et₃N (53 mL) dropwise and the temperature wasraised to 0° C. over a period of one hour. To the reaction mixture wasadded water and 2N HCl and the mixture was extracted with methylenechloride. The organic layer was washed by water and brine, dried overanhydrous magnesium sulfate to afford the desired aldehyde as yellowoil, which will be used in the next step quickly without purification.R_(f) 0.7 (EtOAC/hexane 1/5).

To a solution of the aldehyde intermediate in THF (50 ml) at −60° C. wasadded dropwise ethynylmagnesium bromide (400 ml, 0.5 M in THF solution)and the solution was stirred for 30 minutes allowing the temperature toreach 0° C. The reaction was quenched at −60° C. with saturated ammoniumchloride solution (40 ml) and warmed to RT. The aqueous layer wasextracted with EtOAc (2×). The combined organic portions were washedwith brine, dried over magnesium sulfate, filtered, and concentrated toafford the desired alcohol as s light yellow oil, which was used quicklyin the next step without purification.

To a solution of the alcohol intermediate (7.86 g, 0.048 mol) in dry DMF(160 mL) was added imidazole (16.25 g, 0.34 mol) andtert-butyldimethylsilyl chloride (18.0 g, 0.119 mol). The mixture wasstirred at room temperature then was quenched with saturated aqueoussolution of ammonium chloride and diluted with ethyl acetate. Theorganic layer was washed with saturated ammonium chloride, water, brine,dried over sodium sulfate, and evaporated in vacuo to give an oilyresidue which was purified by flash column chromatography to afford thetitle compound (3.44 g) as colorless oil. ¹H NMR (CDCl₃) δ 0.10 (m, 2H),0.11 (s, 3H), 0.15 (s, 3H), 0.44 (d, J=7.69 Hz, 2H), 0.71 (m, 1H), 0.91(s, 9H), 1.36 (d, J= Hz, 2H), 1.80 (m, 4H), 2.08 (m, 2H), 2.30 (s, 1H),4.40 (s, 1H).

Intermediate 2.4:4-{[tert-butyl(dimethyl)silyl]oxy}-4-[1-(cyclopropylmethyl)cyclobutyl]but-2-yn-1-ol.

To a solution of intermediate 2.3 (3.44 g, 12.4 mmol) in THF (100 ml) at−78° C. was added dropwise n-BuLi (9.3 ml, 1.6 M in hexane) over aperiod of 10 minutes. The reaction mixture was stirred for 30 minutesbefore paraformaldehyde (1.49 g, 49.6 mmol) was added in one portion.After the mixture was stirred for 10 minutes, the cooling bath wasremoved and the mixture was stirred at RT for 18 hours. The resultingmixture was treated with saturated ammonium chloride and EtOAc. Theorganic layer was washed with water and brine, dried with magnesiumsulfate, concentrated and purified by flash column chromatography toafford the title compound (2.37 g, 52%) as colorless oil. R_(f) 0.6(EtOAc/hexane 1/4) ¹H NMR (CDCl₃) δ 0.10 (m, 2H), 0.11 (s, 3H), 0.15 (s,3H), 0.44 (m, 2H), 0.71 (m, 1H), 0.91 (s, 9H), 1.31 (m, 1H), 1.62 (m,1H), 2.04 (m, 4H), 4.28 (s, 2H), 4.43 (s, 1H).

Intermediate 2.5:4-{[tert-butyl(dimethyl)silyl]oxy}-4-[1-cyclopropylmethyl)-cyclobutyl]butan-1-ol.

A heterogeneous mixture of intermediate 2.4 (2.3 g) and 10% Pd/C(catalytic amount) in MeOH (20 mL) was stirred in an atmosphere ofhydrogen for 3 h. The solvent was filtered via celite, concentrated invacuo to give a residue used in the next step without furtherpurification (2.2 g, 95%): R_(f) 0.10 (EtOAc/hexane 1/9).

Intermediate 2.6:4-{[tert-butyl(dimethyl)silyl]oxy}-4-[1-(cyclopropylmethyl)-cyclobutyl]butanal.

A solution of oxalyl chloride in DCM (10 mL, 2.0 M, 2.1 mmol,) wasdiluted with dry DCM (10 mL) and cooled to −70° C. and a solution ofDMSO (0.18 mL, 2.6 mmol) in DCM (5 mL) was added dropwise. After 15min., to the above solution was added dropwise a solution ofintermediate 2.5 (0.50 g, 1.6 mmol) in DCM (5 mL). The resultingsolution was stirred at −78° C. for 45 min. then Et₃N (1.1 mL, 8.0 mmol)was added and the solution was warmed to RT. After 15 min. the solutionwas diluted with DCM (50 mL) and washed with a saturated solution ofNH₄Cl (2×50 mL), brine (50 mL), dried over sodium sulfate andconcentrated in vacuo to afford the aldehyde intermediate (0.37 g, 80%)used in the next step without further purification. R_(f) 0.40(EtOAc/hexane 1/9).

Intermediate 2.7: rac.Methyl(5Z)-7-((2R,3R)-1-{4-{[tert-butyl(dimethyl)silyl]-oxy}-4-[1-(cyclopropylmethyl)cyclobutyl]butyl}-3-chloropyrrolidin-2-yl)hept-5-enoate.

To a solution of intermediate 2.6 (0.37 g, 1.16 mmol) and intermediate1.9 (0.28 g, 1.16 mmol) in MeOH (10 mL) was added a solution of NaCNBH₃in THF (2.3 mL, 1.0 M, 2.32 mmol). The resulting solution was stirred atRT for 18 h then was concentrated in vacuo, diluted with EtOAc (50 mL)and washed with a saturated solution of NaHCO₃ (50 mL), and brine (50mL). The organic solution was dried over sodium sulfate and concentratedin vacuo. The crude residue was subjected to flash chromatography andwas eluted with EtOAc/hexane to afford the desired intermediate (0.64 g,99%) as colorless oil. R_(f) 0.60 (EtOAc/hexane 1/4); MS (m/z): 540(M+1).

Intermediate 2.8 and 2.9: rac.Methyl(5Z)-7-(3-chloro-1-{4-[1-(cyclopropyl-methyl)cyclobutyl]-4-hydroxybutyl}pyrrolidin-2-yl)hept-5-enoate.

Intermediate 2.7 (0.64 g, 1.19 mmol) was diluted with HCl in dioxanesolution (10 mL. 4M). The solution was stirred at 0° C. for 2 h thenconcentrated under reduced pressure. The crude residue was diluted withEtOAc (50 mL) and washed with a saturated solution of NaHCO₃ (20 mL) andbrine (20 mL). The organic phase was dried over sodium sulfate andconcentrated under reduced pressure. Silica gel column chromatographyeluted with EtOAc/hexane allowed the separation of the twodiastereoisomers intermediate. Intermediate 2.8 (first isomer, 70 mg):R_(f) 0.4 (EtOAc/hexane 1/1); Intermediate 2.9 (second isomer, 90 mg):R_(f) 0.35 (EtOAc/hexane 1/1).

The title compound,(5Z)-7-(-3-chloro-1-{4-[1-(cyclopropylmethyl)cyclobutyl]-4-hydroxybutyl}pyrrolidin-2-yl)hept-5-enoicacid, was then prepared as follows. To a solution of intermediate 2.8(81 mg, 0.19 mmol) in MeOH (0.9 mL) and THF (0.9 mL) was added asolution of NaOH in water (0.29 mL, 1.0 M, 0.29 mmol). The resultingsolution was stirred at RT for 20 h, and then was concentrated underreduced pressure. The crude residue was diluted with water (10 mL) andwashed with ether (2×10 mL). The aqueous solution was lyophilized toobtain the desired compound (50 mg) as a pale yellow solid.

The title compound, rac.(5Z)-7-(-3-chloro-1-{4-[1-(cyclopropylmethyl)cyclo-butyl]-4-hydroxybutyl}pyrrolidin-2-yl)hept-5-enoicacid, was then prepared as follows. To a solution of intermediate 2.9(100 mg, 0.23 mmol) in acetonitrile (5 mL) was added hydrochloric acid(5 mL, 6M solution). The resulting solution was stirred at RT for 24 hthen lyophilized to afford the desired compound (110 mg) as a whitesolid. MS (m/z) 413 (M+1).

Example 3 Preparation of rac.(5Z)-7-{(3R)-3-chloro-1-[(2E)-4-hydroxynon-2-enyl]pyrrolidin-2-yl}hept-5-enoicacid (Scheme 2, Steps A, B, I, E, and F)

Intermediate 3.1: (2E)-4-{[tert-butyl(dimethyl)silyl]oxy}non-2-en-1-ol.

To a solution of intermediate (R)-1.11 (236.1 mg, 0.874 mmol) in ether(5.0 mL), cooled in an ice-water bath, was added a solution of sodiumbis(2-methoxyethoxy) aluminum hydride (Red-Al) in toluene (0.320 mL, 65%wt. in toluene) by syringe dropwise. The mixture is stirred for 5 h andthe reaction quenched with a Rochelle salt, diluted with ethyl acetate(20 mL). The organic layer is washed with water, brine, dried oversodium sulfate, evaporated to give a colorless oily residue (0.216 g,0.794 mmol, 90.8%). R_(f) 0.10 (EtOAc/hexane 1/9).

Intermediate 3.2:{[(2E)-4-bromo-1-pentylbut-2-enyl]oxy}(tert-butyl)di-methylsilane.

To a solution of intermediate 3.1 (0.216 g, 0.794 mmol, 1.0 eq) in DCM(9.0 mL, 0.12 M) were added CBr₄ (0.289 g, 0.873 mmol, 1.1 eq) followedby PPh₃ (0.249 g, 0.952 mmol, 1.2 eq). The resulting solution wasstirred at RT for 1/2 h and then concentrated in vacuo. The crudeproduct was purified by flash column chromatography (hexanes) to affordfractions of the desired compound (0.208 g, 0.622 mmol, 78.4%) as acolorless oil. R_(f) 0.68, (EtOAc/hexanes 1/9).

Intermediate 3.3: rac.Methyl(5Z)-7-{(3R)-3-chloro-1-[(2E)-4-(1,1,2,2-tetra-methylpropoxy)non-2-enyl]pyrrolidin-2-yl}hept-5-enoate.

To a solution of intermediate 3.2 (0.175 g, 0.524 mol) in DMF (3.0 mL,0.1 M) were added the intermediate 1.9 (0.130 g, 0.524 mmol) and K₂CO₃(275 mg, 1.99 mmol). The resulting mixture was stirred at 60° C. for 18h and then diluted with EtOAc (25 mL). The organic layer was washed witha saturated solution of NH₄Cl (2×10 mL), water (4×10 mL), brine (2×10mL), dried over sodium sulfate, filtered, and evaporated in vacuo togive a crude product (311.2 mg) which on flash column chromatography(EtOAc/hexanes 3/7) gave fractions of the desired compound (241.2 mg,0.483 mmol, 92.2%) as a yellow oil, R_(f) 0.68, (EtOAc/hexanes 1/9).

Intermediate 3.4: rac.Methyl(5Z)-7-{(3R)-3-chloro-1-[(2E)-4-hydroxynon-2-enyl]pyrrolidin-2-yl}hept-5-enoate.

Intermediate 3.3 (122.0 mg, 0.236 mmol) was dissolved in a 4M HClsolution in dioxane (10 mL). The resulting solution was stirred for 1 hrat RT and then concentrated in vacuo to afford the title compound (0.10g, 97.5%).

The title compound, rac.(5Z)-7-{(3R)-3-chloro-1-[(2E)-4-hydroxynon-2-enyl]-pyrrolidin-2-yl}hept-5-enoicacid, was then prepared as follows. To a solution of intermediate 3.4(93.0 mg, 0.241 mmol) in MeOH (1.1 mL), THF (1.1 mL), and 1M solution ofNaOH in water (0.36 mL, 0.362 mol). The resulting solution was stirredat RT for 18 h then concentrated under reduced pressure to give thesodium salt. The sodium salt was dissolved in water (10 mL) and organicresidue extracted with EtOAc (10 mL×2). The water layer was concentratedon a rotary evaporator to give a solid residue. This residue wasdissolved in water and subjected to lyophilized to afford the titlecompound (55.4 mg, 0.123 mmol, 49%) as a colorless oil. MS (m/z) 372(M+1).

Example 4 Preparation of: rac.(5Z)-7-{(3R)-3-chloro-1-[(2Z)-4-hydroxynon-2-enyl]pyrrolidin-2-yl}hept-5-enoicacid (Scheme 2, Steps A, B, I, E, and F)

Intermediate 4.1: (2Z)-4-{[tert-butyl(dimethyl)siloxy]oxy}non-2-en-1-ol.

To a solution of intermediate 1.11 (423.3 mg, 1.556 mmol), in DCM (20.0mL) was hydrogenated in the presence of Pd/CaCO₃/lead (42.5 mg, Lindlarcatalyst). The heterogeneous mixture is stirred for 3.5 h and thenfiltered via celite. The filtrate is evaporated to give a glassy residue(0.354 g, 1.29 mmol, 83.2%). R_(f) 0.10 (EtOAc/hexane 1/9).

The title compound, rac.(5Z)-7-{(3R)-3-chloro-1-[(2Z)-4-hydroxynon-2-enyl-]pyrrolidin-2-yl}hept-5-enoicacid was then prepared from intermediate 4.1 and intermediate 1.9 usingthe procedure of Example 3. MS (m/z) 372 (M+1).

Example 5a and 5b Preparation of methyl(5Z)-7-[(2R)-1-(3-hydroxyoctyl)-3-oxopyrrolidin-2-yl]hept-5-enoate(Scheme 1, Steps A-H)

Intermediate 5.1:tert-butyl2-[(2Z)-7-methoxy-7-oxohept-2-enyl]-3-oxo-pyrrolidin-1-carboxylate.

A DCM solution of oxalyl chloride (1.0 mL, 2.0 M, 2.0 mmol) was dilutedwith dry DCM (15 mL) and cooled to −70° C. then a solution of DMSO (0.17mL, 2.44 mmol) in DCM (7 mL) was added dropwise. After 15 min. to thissolution was added dropwise a solution of intermediate 1.6 (0.5 g, 1.53mmol) in DCM (7 mL). The resulting solution was stirred at −70° C. for45 min. then Et₃N (1.06 mL, 7.6 mmol) was added dropwise and thesolution warmed to RT. After 15 min. the solution was diluted with DCM(50 mL) and washed with a saturated solution of NH₄Cl (2×50 mL), brine(50 mL), dried over sodium sulfate and concentrated in vacuo to affordthe aldehyde intermediate (0.49 g, 98%) used in the next step withoutfurther purification. R_(f) 0.75 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ1.48 (s, 9H), 1.50-1.75 (m, 4H), 2.00-2.15 (m, 2H), 2.28 (t, 2H),2.35-2.70 (m, 4H), 3.45-3.55 (m, 1H), 3.65 (s, 3H), 3.90-4.05 (m, 2H),5.25-5.55 (m, 2H).

Intermediate 5.2: methyl(5Z)-7-(3,3-dimethoxypyrrolidin-2-yl)hept-5-enoate.

A solution of intermediate 5.1 (200 mg, 0.62 mmol), trimethylorthoformate (0.86 mL, 7.86 mmol), and H₂SO₄ (0.03 mL) in MeOH (3 mL)was stirred at RT for 24 h. The solution was then concentrated in vacuo,diluted with EtOAc (50 mL) and washed with saturated solution of NaHCO₃(30 mL), and brine (30 mL). The organic solution was dried andconcentrated under reduced pressure to afford the desired intermediate(160 mg, 98%) as a pale yellow oil used in the next step withoutpurification. ¹H NMR (CDCl₃) δ 1.60-1.74 (m, 2H), 1.80-2.20 (m, 6H),2.22-2.38 (m, 3H), 2.85-2.95 (m, 1H), 2.96-3.07 (m, 1H), 3.20 (s, 3H),3.26 (s, 3H), 3.67 (s, 3H), 5.35-5.55 (m, 2H); MS (m/z) 272 (M+1).

Intermediate 5.3:methyl(5Z)-7-[(2S)-3,3-dimethoxypyrrolidin-2-yl]hept-5-enoate.

To a solution of intermediate 5.2 (1.50 g, 5.5 mmol) in i-PrOH (13 mL)was added a solution of D-tartaric acid (0.83 g, 5.5 mmol) in i-PrOH (12mL). The mixture was stirred at RT for 2 h then at 0 C for 30 min. Thewhite precipitate was filtered out and washed with small amount ofi-PrOH. The residue was diluted with EtOAc and washed with a saturatedsolution of NaHCO₃, brine, dried and concentrated in vacuo to afford thedesired chiral amine (0.38 g).

Intermediate 5.4: methyl(5Z)-7-[(2S)-3,3-dimethoxy-1-(3-oxooctyl)pyrrolidin-2-yl]hept-5-enoate.

To a solution of intermediate 5.3 (100 mg, 0.37 mmol) in MeOH (10 mL)was added 1-octen-3-one (0.17 mL, 1.11 mmol). The resulting solution wasstirred at reflux for 2 h, then was concentrated in vacuo. The cruderesidue was subjected to flash chromatography and was eluted withEtOAc/hexane to afford the desired intermediate (130 mg, 89%) ascolorless oil. R_(f) 0.75 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ 0.87 (t,3H), 1.20-1.35 (m, 4H), 1.63-1.75 (m, 2H), 1.80-2.00 (m, 2H), 2.00-2.15(m, 4H), 2.20-2.60 (m, 10H), 2.95-3.10 (m, 2H), 3.13 (s, 3H), 3.20 (s,3H), 3.65 (s, 3H), 5.31-5.58 (m, 2H); MS (m/z) 398 (M+1).

Intermediate 5.5 and 5.6:methyl(5Z)-7-[(2S)-1-(3-hydroxyoctyl)-3,3-di-methoxypyrrolidin-2-yl]hept-5-enoate.

To a mixture of intermediate 5.4 (0.12 g, 0.30 mmol) in MeOH (4 mL) andwater (5 mL) were added CeCl₃ (75 mg, 0.30 mmol) followed by NaBH₄ (23mg, 0.60 mmol). After 1 h the reaction was diluted with EtOAc (20 mL)and washed with a saturated solution of NaHCO₃ (20 mL), brine (20 mL),dried and concentrated in vacuo to afford a mixture of the 2diastereoisomers intermediate that were separated by silica gel flashcolumn chromatography (EtOAc/hexane). Intermediate 5.5 (50 mg): R_(f)0.30 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ 0.87 (t, 3H), 1.20-1.50 (m,10H), 1.51-1.86 (m, 4H), 1.90-2.00 (dd, 1H), 2.05-2.20 (m, 4H),2.30-2.45 (m, 4H), 2.50-2.60 (m, 1H), 2.90-3.02 (m, 1H), 3.11 (s, 3H),3.20 (s, 3H), 3.25 (t, 1H), 3.64 (s, 3H), 3.66-3.80 (m, 1H), 5.33-5.57(m, 2H); MS (m/z) 400 (M+1). Intermediate 5.6 (50 mg): R_(f) 0.20(EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ 0.85 (t, 3H), 1.20-1.55 (m, 10H),1.61-1.80 (m, 4H), 1.92-2.20 (m, 4H), 2.22-2.40 (m, 3H), 2.45-2.60 (m,2H), 2.90-3.02 (m, 1H), 3.11 (s, 3H), 3.20 (s, 3H), 3.12 (t, 1H), 3.64(s, 3H), 3.66-3.80 (m, 1H), 5.33-5.57 (m, 2H); MS (m/z) 400 (M+1).

The title compound, methyl(5Z)-7-[(2R)-1-(3-hydroxyoctyl)-3-oxopyrrolidin-2-yl]hept-5enoate, wasthen prepared as follows. To a solution of intermediate 3.7 (50 mg, 0.13mmol) in THF (2 mL) and H₂O (0.2 mL) was added a solution of HCl indioxane (2 mL, 4M solution). The resulting solution was stirred at roomtemperature for 2 hours then concentrated in vacuo to afford the desiredcompound (29 mg, 66%), MS (m/z) 354 (M+1).

The title compound, methyl(5Z)-7-[(2R)-1-(3-hydroxyoctyl)-3-oxopyrrolidin-2-yl]hept-5-enoate, wasthen prepared as follows. To a solution of intermediate 3.8 (50 mg, 0.13mmol) in THF (2 mL) and H₂O (0.2 mL) was added a solution of HCl indioxane (2 mL, 4M solution). The resulting solution was stirred at RT 2h then concentrated in vacuo to afford the desired compound (32 mg,70%). MS (m/z) 354 (M+1).

Example 6 Preparation of rac.4-{[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]methoxy}benzoic acid(Scheme 3, Steps A-F)

Intermediate 6.1: rac. 1-tert-butyl2-ethyl(2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate.

To a solution of the 3-oxo-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester (obtained from diethyl3-azahexane-1,6-dicarboxylate according to the procedure of Cooper, J.et al. J. Chem. Soc. Perkin Trans. 1, 1993, 1313-1317) (15.0 g, 0.058mol) in THF (600 mL) cooled at −78° C. was added dropwise a THF solutionof L-Selectride (58 mL, 1 M, 0.058 mol). The solution was stirred at−78° C. for 1 h then the reaction was quenched with hydrogen peroxidesolution (35 mL, 30%) and the reaction mixture was allowed to warm up to0° C. The reaction was then diluted with EtOAc and washed with HCl 1M,brine, dried over sodium sulfate and concentrated in vacuo. The cruderesidue was purified by silica gel flash column chromatography usingEtOAc/hexane as eluent to afford the desired intermediate (10 g, 66%) asa colorless oil. R_(f) 0.50 (EtOAc/hexane 4/1); ¹H NMR (CDCl₃) δ1.20-1.35 (t, 3H), 1.44 (s, 9H), 1.95-32 (m, 2H), 3.40-3.70 (m, 2H),4.10-4.42 (m, 3H), 4.55-4.65 (m, 1H); MS (m/z) 260 (M+1).

Intermediate 6.2:1-tert-butyl2-ethyl3-{[(4-methylphenyl)sulfonyl]-oxy}pyrrolidine-1,2-dicarboxylate.

To a solution of intermediate 6.1 (7.0 g, 0.028 mol) in pyridine (50 mL)cooled at 0 C was added portionwise p-toluenesulfonyl chloride (10.4 g,0.054 mol). The resulting solution was stirred at RT for 20 h thenconcentrated in vacuo. The crude residue was diluted with EtOAc (200 mL)and washed with HCl 1M (200 mL), water (100 mL), saturated solution ofNaHCO₃ (200 mL), and brine (200 mL). The organic solution was dried andconcentrated under reduced pressure. The crude mixture was purified bysilica gel flash column chromatography using EtOAc/hexane as eluent toafford the desired intermediate (7.2 g, 63%) as a colorless oil. R_(f)0.50 (EtOAc/hexane 3/7); ¹H NMR (CDCl₃) δ 1.25 (t, 3H), 1.38 (s, 9H),2.00-2.30 (m, 2H), 2.44 (s, 3H), 3.40-3.70 (m, 2H), 4.05-4.25 (m, 2H),4.41 (d, 1H), 5.10-5.20 (m, 1H), 7.34 (d, 2H), 7.76 (d, 2H).

Intermediate 6.3: 1-tert-butyl2-ethyl3-chloropyrrolidine-1,2-dicarboxylate.

To a solution of intermediate 6.2 (72 g, 0.017 mol) in toluene (500 mL)was added tetrabutylammonium chloride (48 g, 0.174 mol). The solutionwas stirred at 60 C for 24 h then diluted with EtOAc (1500 mL) andwashed with water (3×), saturated solution of NaHCO₃ (2×), and brine(1×). The organic solution was dried and concentrated in vacuo to affordthe desired intermediate (5.8 g) as a pale yellow oil used in the nextstep without further purification. R_(f) 0.70 (EtOAc/hexane 3/7); ¹H NMR(CDCl₃) δ 1.25-1.32 (m, 3H), 1.44 (s, 9H), 2.10-2.20 (m, 1H), 2.30-2.42(m, 1H), 3.60-3.75 (m, 2H), 4.15-4.25 (m, 2H), 4.37-4.65 (m, 2H).

Intermediate 6.4:tert-butyl3-chloro-2-(hydroxymethyl)pyrrolidine-1-carbo-xylate.

To a solution of intermediate 6.3 (5.8 g, 0.021 mol) in THF (36 mL) andMeOH (4 mL) was added portionwise NaBH₄ (0.95 g, 0.025 mol). Theresulting mixture was stirred at RT for 1 h then was diluted with EtOAc(150 mL) and washed with a saturated solution of NaHCO₃ and brine. Theorganic solution was dried over sodium sulfate and concentrated invacuo. The crude residue was purified by silica gel flash columnchromatography using EtOAc/hexane as eluent to afford the desiredintermediate (3.0 g, 75% from intermediate #0.2) as a colorless oil.R_(f) 0.30 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ 1.51 (s, 9H), 2.05-2.15(m, 1H), 2.30-2.42 (m, 1H), 3.40-3.80 (m, 5H), 4.00-4.30 (m, 2H).

Intermediate 6.5:tert-butyl-3-chloro-2-{[4-(methoxycarbonyl)phenoxy]methyl}pyrrolidine-1-carboxylate.

To a solution of intermediate 6.4 (250 mg, 1.06 mmol), 4-hydroxybenzoate(161 mg, 1.06 mmol), and triphenylphosphine (307 mg, 1.17 mmol) in THF(10 mL) was added DEAD (0.18 mL, 1.17 mmol). The resulting solution wasstirred at RT for 18 h then concentrated under reduced pressure. Thecrude residue was subjected to flash chromatography and was eluted withEtOAc/hexane to afford the desired intermediate (80 mg, 20%) as acolorless oil. R_(f) 0.75 (EtOAc/hexane 3/7); ¹H NMR (CDCl₃) δ 1.51 (s,9H), 2.10-2.20 (m, 1H), 2.40-2.55 (m, 1H), 3.45-3.80 (m, 2H), 3.87 (s,3H), 3.90-4.10 (m, 1H), 4.14-4.40 (m, 2H), 4.50-4.60 (m, 1H), 6.91 (d,2H), 7.96 (d, 2H).

Intermediate 6.6: methyl 4-[(3-chloropyrrolidin-2-yl)methoxy]benzoate.

Intermediate 6.5 (60 mg, 0.162 mmol) was dissolved in a solution of HClin dioxane (2 mL, 4M HCl solution). The resulting mixture was stirred atRT for 1 h then concentrated in vacuo to afford the desired intermediate(50 mg, 98%) used in the next step without purification. MS (m/z) 270(M+1).

Intermediate 6.7: methyl4-{[3-chloro-1-(3-oxooctyl)pyrrolidin-2-yl]-methoxy}benzoate.

To a solution of intermediate 6.6 (50 mg, 0.162 mmol) in EtOH (5 mL)were added 1-octen-3-one (0.072 mL, 0.49 mmol) and Et₃N (0.090 mL, 0.65mmol). The resulting solution was stirred at reflux for 2 h, then wasconcentrated in vacuo. The crude residue was subjected to flashchromatography and was eluted with EtOAc/hexane to afford the desiredintermediate (60 mg, 90%) as a colorless oil. R_(f) 0.70 (EtOAc/hexane3/7); ¹H NMR (CDCl₃) δ 0.85 (t, 3H), 1.15-1.35 (m, 4H), 1.50-1.60 (m,2H), 2.00-2.10 (m, 1H), 2.25-2.40 (m, 1H), 2.40 (t, 2H), 2.50-2.70 (m,2H), 2.70-2.87 (m, 2H), 3.10-3.30 (m, 3H), 3.82 (dd, 1H), 3.87 (s, 3H),3.97 (dd, 1H), 4.28-4.35 (m, 1H), 6.90 (d, 2H), 7.97 (d, 2H); MS (m/z)396 (M+1).

Intermediate 6.8: methyl4-{[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]methoxy}benzoate.

To a mixture of intermediate 6.7 (0.1 g, 0.25 mmol) in EtOH (3 mL) andwater (3 mL) were added CeCl₃ (62 mg, 0.25 mmol) followed by NaBH₄ (15mg, 0.38 mmol). After 1 h the reaction was diluted with EtOAc (20 mL)and washed with a saturated solution of NaHCO₃ (20 mL), brine (20 mL),dried and concentrated in vacuo to afford a mixture of the 2diastereoisomers intermediate (80 mg, 80%) used in the next step withoutfurther purification. R_(f) 0.50 and 0.45 (EtOAc/hexane 1/1); MS (m/z)398 (M+1).

The title compound,4-{[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2yl]methoxy}benzoic acid, thenwas prepared as follows. To a solution of intermediate 6.8 (80 mg, 0.20mmol) in water (0.4 mL), MeOH (1.2 mL), and THF (1.2 mL) was added NaOH(32 mg, 0.8 mmol). The resulting solution was stirred at roomtemperature for 5 h then concentrated under reduced pressure. The crudemixture was purified by RP-HPLC using ACN/H₂O/0.1% TFA to afford thedesired compound (150 mg, 60%) as a colorless oil. ¹H NMR (D2O) δ0.75-0.85 (m, 3H), 1.15-1.50 (m, 4H), 1.75-2.05 (m, 2H), 2.40-2.50 (m,1H), 2.64-2.75 (m, 1H), 3.40-3.75 (m, 5H), 3.90-4.00 (m, 1H), 4.25-4.35(m, 1H), 4.40-4.50 (m, 1H), 4.55-4.65 (m, 1H), 7.09 (d, 2H), 8.01 (d,2H); MS (m/z) 384 (M+1).

Example 7a and 7b Synthesis of5-({[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]methoxy}methyl)-2-furoicacid (Scheme 3, Steps A-C and M-N)

Intermediate 7.1: tert-butyl3-chloro-2-({[5-(methoxycarbonyl)-2-furyl]methoxy}methyl)pyrrolidine-1-carboxylate.

NaH (36 mg, 0.89 mmol) was added portionwise and at 0 C to a solution ofintermediate 4.4 (200 mg, 0.85 mmol) in DMF (5.0 mL). After 10 min.,methyl 5-bromomethylfuran-2-carboxylate (300 mg, 1.27 mmol) was added.The resulting solution was stirred at RT for 20 h then was diluted withether (50 mL) and washed with HCl 1N (30 mL), water (30 mL), and brine(30 mL). The organic solution was dried and concentrated in vacuo. Thecrude residue was subjected to flash chromatography and was eluted withEtOAc/hexane to afford the desired intermediate (200 mg, 63%) as acolorless oil. R_(f) 0.50 (EtOAc/hexane 3/7); ¹H NMR (CDCl₃) δ 1.45 (s,9H), 2.00-2.12 (m, 1H), 2.30-2.45 (m, 1H), 3.30-3.70 (m, 4H), 3.88 (s,3H), 3.95-4.15 (m, 1H), 4.42-4.51 (m, 1H), 4.51 (s, 2H), 6.41 (s, 1H),7.13 (s, 1H).

Intermediate 7.2: methyl5-{[(3-chloropyrrolidin-2-yl)methoxy]methyl}-2-furoate.

Intermediate 7.1 (200 mg, 0.54 mmol) was dissolved in a solution of HClin dioxane (3 mL, 4M HCl solution). The resulting solution was stirredat RT for 1 h then concentrated in vacuo to afford the desiredintermediate (160 mg, 98%) used in the next step without purification.MS (m/z) 274 (M+1).

Intermediate 7.3: methyl5-({[3-chloro-1-(3-oxooctyl)pyrrolidin-2-yl]methoxy}methyl)-2-furoate.

To a solution of intermediate 7.2 (160 mg, 0.54 mmol) in EtOH (10 mL)were added 1-octen-3-one (0.24 mL, 1.61 mmol) and Et₃N (0.30 mL, 2.14mmol). The resulting solution was stirred at reflux for 2 h, then wasconcentrated in vacuo. The crude residue was subjected to flashchromatography and was eluted with EtOAc/hexane to afford the desiredintermediate (200 mg, 97%) as a colorless oil. R_(f) 0.75 (EtOAc/hexane1/1); ¹H NMR (CDCl₃) δ 0.87 (t, 3H), 1.18-1.35 (m, 4H), 1.50-1.62 (m,2H), 1.94-2.00 (m, 1H), 2.18-2.30 (m, 1H), 2.39 (t, 2H), 2.54-2.76 (m,4H), 2.82-2.92 (m, 1H), 3.04-3.18 (m, 2H), 3.34-3.40 (dd, 1H), 3.45-3.52(dd, 1H), 3.88 (s, 3H), 4.18-4.26 (m, 1H), 4.52 (s, 2H), 6.42 (s, 1H),7.12 (s, 1H); MS (m/z) 400 (M+1).

Intermediate 7.4 and 7.5: methyl5-({[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]methoxy}methyl)-2-furoate.

To a mixture of intermediate 7.3 (0.19 g, 0.48 mmol) in EtOH (6 mL) andwater (6 mL) were added CeCl₃ (117 mg, 0.48 mmol) followed by NaBH₄ (27mg, 0.71 mmol). After 1 h the reaction was diluted with EtOAc (20 mL)and washed with a saturated solution of NaHCO₃ (20 mL), brine (20 mL),dried and concentrated in vacuo to afford a mixture of the 2diastereoisomers intermediate that were separated by silica gel flashcolumn chromatography (EtOAc/hexane). Intermediate 7.4 (70 mg): R_(f)0.30 (EtOAc/hexane 1/1); MS (m/z) 402 (M+1). Intermediate 7.5 (80 mg):R_(f) 0.25 (EtOAc/hexane 1/1); MS (m/z) 402 (M+1).

The title compound,5-({[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]methoxy}methyl)-2-furoicacid, then was prepared as follows. To a solution of intermediate 7.4(70 mg, 0.17 mmol) in water (0.4 mL), MeOH (1.2 mL), and THF (1.2 mL)was added NaOH (27 mg, 0.70 mmol). The resulting solution was stirred atRT for 4 h then was acidified with HCl 1N and concentrated under reducedpressure. The crude mixture was purified by RP-HPLC using ACN/H₂O/0.1%TFA to afford the desired compound (54 mg) as a colorless oil. ¹H NMR(CD3OD) δ 0.85-0.95 (t, 3H), 1.2-1.55 (m, 8H), 1.70-1.95 (m, 2H),2.30-2.42 (m, 1H), 2.50-2.65 (m, 1H), 3.35-4.00 (m, 8H), 4.50-4.60 (m,1H), 4.67 (s, 2H), 6.62 (s, 1H), 7.18 (s, 1H); MS (m/z) 388 (M+1).

The title compound,5-({[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]-methoxy}methyl)-2-furoicacid, men was prepared as follows. To a solution of intermediate 7.5 (80mg, 0.20 mmol) in water (0.4 mL), MeOH (1.2 mL), and THF (1.2 mL) wasadded NaOH (32 mg, 0.80 mmol). The resulting solution was stirred at RTfor 4 h then was acidified with HCl 1N and concentrated under reducedpressure. The crude mixture was purified by RP-HPLC using ACN/H₂O/0.1%TFA to afford the desired compound (74 mg) as a colorless oil. ¹H NMR(CD3OD) δ 0.85-0.95 (t, 3H), 1.20-1.55 (m, 8H), 1.70-1.95 (m, 2H),2.30-2.42 (m, 1H), 2.50-2.65 (m, 1H), 3.35-4.00 (m, 8H), 4.50-4.60 (m,1H), 4.60 (s, 2H), 6.62 (s, 1H), 7.18 (s, 1H); MS (m/z) 388 (M+1).

Example 8a and 8b Preparation of4-{2-[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]ethyl}benzoic acid(Scheme 3, Steps A-C and G-L)

Intermediate 8.1: tert-butyl 3-chloro-2-{(E,Z)-2-[4(methoxycarbonyl)-phenyl]vinyl}pyrrolidine-1-carboxylate.

Step A (Swern Oxidation):

A DCM solution of oxalyl chloride (1.4 mL, 2.0 M, 2.77 mmol) was dilutedwith anhydrous DCM (15 mL) and cooled to −70° C. then a solution of DMSO(0.24 mL, 3.40 mmol) in DCM (7 mL) was added dropwise. After 15 min. tothis solution was added dropwise a solution of intermediate 6.4 (0.50 g,2.13 mmol) in DCM (7 mL). The resulting solution was stirred at −70° C.for 45 min. then Et₃N (1.50 mL, 10.6 mmol) was added dropwise and thesolution warmed to RT. After 15 mm, the solution was diluted withdichloromethane (50 mL) and washed with a saturated solution of NH₄Cl(2×50 mL), brine (50 mL), dried over sodium sulfate and concentrated invacuo to afford the aldehyde intermediate (0.49 g, 98%) used in the nextstep without further purification. R_(f) 0.37 (EtOAc/hexane 3/7).

Step B (Wittig Reaction):

(4-Methoxycarbonylbenzyl)triphenylphosphonium bromide (1.36 g, 2.77mmol) was added portionwise and at 0° C. to a solution of NaHMDS (3.0mL, 1.0 M in THF, 3.0 mmol) in THF (10 mL). After 15 min. was added asolution of the aldehyde intermediate (0.49 g, 2.12 mmol) in THF (10mL). The resulting mixture was stirred at RT for 18 h then was dilutedwith EtOAc (600 mL) and washed with HCl 1M solution (60 mL) and brine(60 mL). The organic phase was dried over sodium sulfate andconcentrated in vacuo. The crude residue was subjected to flashchromatography and was eluted with EtOAc/hexane to afford the desiredolefin intermediate (600 mg, 77%) as colorless oil. R_(f) 0.45(EtOAc/hexane 3/7); MS (m/z) 366 (M+1).

Intermediate 8.2: tert-butyl3-chloro-2-{2-[4-(methoxycarbonyl)phenyl]ethyl}pyrrolidine-1-carboxylate.

A mixture of intermediate 8.1 (500 mg, 1.36 mmol) and Pd/C (cat Amount)in MeOH (15 mL) was vigorously stirred under H₂ atmosphere (1 atm) for25 min. Filtration through celite pad and concentration under reducedpressure gave the desired intermediate (500 mg, 98%) as a colorless oilused in the next step without further purification. R_(f) 0.50(EtOAc/hexane 3/7); ¹H NMR (CDCl₃) δ 1.44 (s, 9H), 1.90-2.40 (m, 2H),2.65-2.82 (m, 2H), 3.40-3.80 (m, 2H), 3.90 (s, 3H), 4.05-4.30 (m, 1H),7.23 (d, 2H), 7.95 (d, 2H); MS (m/z) 368 (M+1).

Intermediate 8.3: methyl 4-[2-(3-chloropyrrolidin-2-yl)ethyl]benzoate.

Intermediate 8.2 (0.5 g, 1.36 mmol) was dissolved in a solution of HClin dioxane (5 mL, 4M HCl solution). The resulting solution was stirredat RT for 1 h then concentrated in vacuo to afford the desiredintermediate (410 mg, 95%) used in the next step without purification.MS (m/z) 268 (M+1).

Intermediate 8.4: methyl4-{2-[3-chloro-1-(3-oxooctyl)pyrrolidin-2-yl]ethyl}benzoate.

To a solution of intermediate 8.3 (206 mg, 0.68 mmol) in EtOH (10 mL)were added 1-octen-3-one (0.30 mL, 2.04 mmol) and Et₃N (0.47 mL, 3.40mmol). The resulting solution was stirred at reflux for 2 h, then wasconcentrated in vacuo. The crude residue was purified by silica gelflash column chromatography using EtOAc/hexane as eluent to afford thedesired intermediate (200 mg, 75%) as a colorless oil. R_(f) 0.40(EtOAc/hexane 3/7); MS (m/z) 394 (M+1).

Intermediates 8.5 and 8.6: methyl4-{2-[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]ethyl}benzoate.

To a mixture of intermediate 8.4 (200 mg, 0.51 mmol) in EtOH (6 mL) andwater (6 mL) were added CeCl₃ (125 mg, 0.51 mmol) followed by NaBH₄ (39mg, 1.02 mmol). After 1 h the reaction was diluted with EtAOc (20 mL)and washed with a saturated solution of NaHCO₃ (20 mL), brine (20 mL),dried and concentrated in vacuo to afford a mixture of the 2diastereoisomers intermediate that were separated by flash columnchromatography (EtOAc/hexane). Intermediate 8.5 (40 mg): R_(f) 0.50(EtOAc/hexane 1/1); MS (m/z) 396 (M+1). Intermediate 8.6 (45 mg): R_(f)0.45 (EtOAc/hexane 1/1); MS (m/z) 396 (M+1).

The title compound,4-{2-[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]ethyl}benzoic acid,then was prepared as follows. To a solution of intermediate 8.5 (45 mg,0.11 mmol) in water (0.67 mL), MeOH (2 mL), and THF (2 mL) was addedNaOH (50 mg, 1.25 mmol). The resulting solution was stirred at RT for 6h then concentrated under reduced pressure. The crude mixture waspurified by RP-HPLC using ACN/H₂O/0.1% TFA to afford the desiredcompound (40 mg, 60%) as a colorless oil. ¹H NMR (CD3OD) δ 0.85-0.95 (m,3H), 1.20-1.45 (m, 8H), 1.61-1.72 (m, 1H), 1.80-1.95 (m, 1H), 2.03-2.25(m, 2H), 2.35-2.45 (m, 1H), 2.55-2.70 (m, 1H), 2.80-3.00 (m, 2H),3.25-3.40 (m, 1H), 3.45-3.95 (m, 5H), 4.67 (br s, 1H), 7.40 (d, 2H),7.97 (d, 2H); MS (m/z) 382 (M+1).

The title compound,4-{2-[3-chloro-1-(3-hydroxyoctyl)pyrrolidin-2-yl]ethyl}benzoic acid,then was prepared from intermediate 8.6 using the procedure of Example8.a. ¹H NMR (CD3OD) δ 0.85-0.95 (m, 3H), 1.20-1.55 (m, 8H), 1.61-1.85(m, 2H), 2.02-2.12 (m, 1H), 2.15-2.28 (m, 1H), 2.35-2.45 (m, 1H),2.55-2.70 (m, 1H), 2.80-3.05 (m, 2H), 3.45-3.95 (m, 6H), 4.71 (br s,1H), 7.40 (d, 2H), 7.97 (<L 2H); MS (m/z) 382 (M+1).

Example 9a and 9b Preparation of(5Z)-7-{(trans-2,3)-3-Chloro-1-[4-hydroxy-4-(1-propylcyclobutyl)butyl]pyrrolidin-2-yl}hept-5-enoicacid (Scheme 2, Steps A-F)

The title compounds were prepared from cyclobutanecarboxylic acid,propyl iodide, and intermediate 1.9 using the procedure of Example 2.

Example 9a: MS (m/z) 400.2 (M+1)Example 9b: MS (m/z) 400.2 (M+1).

Example 10 Preparation of4-{3-chloro-1-[(4R)-4-hydroxynonyl]pyrrolidin-2-yl}ethyl)benzoic acid(Scheme 3, Steps A-C and G-L)

The title compound was prepared as the TFA salt from intermediate 8.3and intermediate 1.13 using the procedure of Example 1. ¹H NMR (CD3OD) δ0.85-0.97 (t, 3H), 1.20-1.65 (m, 10H), 1.68-1.95 (m, 2H), 2.02-2.13 (m,1H), 2.13-2.26 (m, 1H), 2.35-2.45 (m, 1H), 2.55-2.70 (m, 1H), 2.82-3.04(m, 2H), 3.20-3.62 (m, 4H), 3.70-3.92 (m, 2H), 4.65-4.75 (m, 1H), 7.40(d, 2H), 7.97 (d, 2H); MS (m/z) 396 (M+1).

Example 11 Preparation of4-(2-{1-[4-(1-butylcyclobutyl)-4-hydroxybutyl]-3-chloropyrrolidin-2-yl}ethyl)benzoicacid (Scheme 3, Steps A-C and G-L)

The title compound was prepared as the TFA salt from intermediate 8.3and 4-(1-butylcyclobutyl)-4-{[tert-butyl(dimethyl)silyl]oxy}butanal(obtained from cyclobutane carboxylic acid and 1-bromobutane asdescribed for intermediate 2.6) using the procedure of Example 1. ¹H NMR(CD3OD) δ 0.85-0.97 (t, 3H), 1.20-1.45 (m, 6H), 1.45-2.25 (m, 12H),2.35-2.45 (m, 1H), 2.55-2.65 (m, 1H), 2.82-3.04 (m, 2H), 3.20-3.62 (m,4H), 3.70-3.88 (m, 2H), 4.65-4.75 (m, 1H), 7.40 (d, 2H), 7.97 (d, 2H);MS (m/z) 436 (M+1).

Example 12 Preparation of7-[1-(3-Hydroxy-4-phenyl-butyl)-3-oxo-pyrrolidin-2-yl]-hept-5-enoic acid(Scheme 4, Steps A-H)

Intermediate 12.1

To a solution of3-(tert-butyl-dimethyl-silanyloxy)-2-methoxycarbonylmethyl-pyrrolidine-1-carboxylicacid benzyl ester (obtained from 3-aminopropanal according to theprocedure of Macdonald et al: J. Med. Chem. 1998, 41(21), 3919-3922))(10.0 g. 0.025 mol) in MeOH (50 mL) was added Pd/C (1.0 g). The mixturewas stirred under hydrogen atmosphere (1 atm) for 4 h, then filteredthrough celite and concentrated under reduced pressure to afford thedesired intermediate (6.0 g, 90%) as a colorless oil used in the nextstep without further purification. ¹H NMR (CDCl₃) δ (mixture ofdiastereoisomers) 0.05 (s, 6H), 0.87 (s, 9H), 1.65-1.82 (m, 1H),1.95-2.05 (m, 1H), 2.3-2.7 (m, 2H), 2.95-3.4 (m, 2H), 3.67-3.68 (2s,3H), 3.90-4.31 (m, 1H); MS (m/z) 274.2 (M+1).

To a solution of the free amine previously obtained (6.0 g, 0.022 mol)in DCM (100 mL) were added di-tert-butyl dicarbonate (3.7 mL, 0.026mol), Et₃N (3.7 mL, 0.026 mol), and DMAP (0.6 g). The resulting solutionwas stirred at RT for 18 h then was washed with HCl 1.0M (2×100 mL) andbrine (100 mL), dried over sodium sulfate and concentrated in vacuo toafford the desired intermediate (8.0 g, 97%) as a pale yellow oil usedin the next step without further purification. R_(f) 0.6 (EtOAc/hexane1/4); ¹H NMR (CDCl₃) δ (mixture of diastereoisomers) 0.04-0.06 (2s, 6H),0.88-0.90 (2s, 9H), 1.42-1.45 (2s, 9H), 1.70-2.20 (m, 2H), 2.55-2.90 (m,2H), 3.30-3.55 (m, 2H), 3.60-3.70 (2s, 3H), 3.8-4.0 (m, 1H).

Intermediate 12.2

To a solution of intermediate 12.1 (7.5 g, 0.02 mol) in dry benzene (150mL) was added dropwise a solution of Red-Al (6.3 mL, 65+wt % solution intoluene, 0.022 mol). This solution was stirred at reflux for 1 h thencooled to RT and quenched with a saturated solution of Rochelle salt.The mixture was extracted with EtOAc (2×150 mL) and the collectedorganic phase was washed with brine (200 mL), dried and concentrated invacuo. The crude mixture of diastereoisomers was purified by silica gelflash column chromatography using EtOAc/hexane as eluent to afford thedesired intermediates

Intermediate 1.2a (cis isomer): R_(f) 0.30 (EtOAc/hexane 1/4); ¹H NMR(CDCl₃) δ 0.06 (s, 6H), 0.88 (s, 9H), 1.2-1.4 (m, 2H), 1.45 (s, 9H),1.90-2.10 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.72 (m, 2H), 4.00-4.10 (m,1H), 4.25-4.40 (m, 2H); MS (m/z): 346 (M+1).Intermediate 1.2b (trans isomer): R_(f) 0.25 (EtOAc/hexane 1/4); ¹H NMR(CDCl₃) δ 0.05 (s, 6H), 0.85 (s, 9H), 1.1-1.2 (m, 1H), 1.45 (s, 9H),1.70-2.00 (m, 2H), 3.30-3.70 (m, 5H), 3.85-4.02 (m, 2H), 4.53 (dd, J=5.5and 9.5 Hz, 1H); MS (m/z): 346 (M+1).

Intermediate 12.3 Step A (Swern Oxydation):

A DCM solution of oxalyl chloride (21.0 mL, 2.0 M, 0.043 mol) wasdiluted with dry DCM (200 mL) and cooled to −70° C. then a solution ofDMSO (3.75 mL, 0.053 mol) in DCM (40 mL) was added dropwise. After 15min. to this solution was added dropwise a solution of intermediate 1.2(11.4 g, 0.033 mol) in DCM (40 mL). The resulting solution was stirredat −70° C. for 45 min. then Et₃N (23.0 mL, 0.165 mol) was added dropwiseand the solution warmed to RT. After 15 min. the solution was dilutedwith DCM (200 mL) and washed with a saturated solution of NH₄Cl (2×300mL), brine (300 mL), dried over sodium sulfate and concentrated in vacuoto afford the aldehyde intermediate (11.2 g, 98%) used in the next stepwithout further purification. R_(f) 0.37 (EtOAc/hexane 1/4); ¹H NMR(CDCl₃) δ 0.06-0.08 (2s, 6H), 0.86 (s, 9H), 1.44 (s, 9H), 1.70-1.95 (m,2H), 2.35-2.45 (m, 1H), 2.58-2.81 (m, 1H), 3.35-3.60 (m, 3H), 3.95-4.10(m, 2H), 9.76 (s, 1H); MS (m/z): 344 (M+1).

Step B (Wittig Reaction):

A suspension of (4-carboxybutyl)triphenylphosphonium bromide (20.0 g,0.044 mol) in THF (250 mL) was cooled to 0° C., then a THF solution ofKO^(t)Bu (90 mL, 1.0M, 0.09 mol) was added dropwise. After 15 min. wasadded a solution of the aldehyde intermediate (10 g, 0.03 mol) in THF(100 mL). The resulting mixture was stirred at RT for 18 h then wasdiluted EtOAc (300 mL) and washed with HCl 1M solution (200 mL) andbrine (200 mL). The organic phase was dried over sodium sulfate andconcentrated in vacuo to afford the crude acid intermediate useddirectly in the next step without former purification.

Step C (Esterification Reaction):

To a solution of the crude acid in DCM (180 mL) and MeOH (42 mL) wasadded dropwise a solution of trimethylsylildiazomethane (50 mL, 2 Msolution in hexane, 12 mmol). The resulting solution was stirred at RTfor 5 h then was concentrated under reduced pressure. The crude residuewas purified by silica gel flash column chromatography usingEtOAc/hexane as eluent to afford the desired ester intermediate 1.5 (8.6g, 66%) as colorless oil. R_(f) 0.50 (EtOAc/hexane 1/4); ¹H NMR (CDCl₃)δ 0.03 (s, 6H), 0.88 (s, 9H), 1.44 (s, 9H), 1.60-1.80 (m, 3H), 1.90-2.10(m, 4H), 2.30 (t, J=7.72 Hz, 2H), 2.30-2.45 (m, 1H), 3.30-3.55 (m, 3H),3.65 (s, 3H), 4.01-4.10 (m, 1H), 5.35-5.50 (m, 2H).

Intermediate 12.4

To a solution of intermediate 12.3 (8.0 g, 0.018 mol) in THF (50 mL) wasadded dropwise a solution of TBAF (20.0 mL, 1.0 M, 0.02 mol) in THF. Theclear solution was stirred at RT for 2 h then was concentrated underreduced pressure. The residue was diluted with EtOAc (200 mL), washedwith water (2×100 mL), brine (100 mL), dried over sodium sulfate andconcentrated in vacuo. The crude residue was purified by silica gelflash column chromatography using EtOAc/hexane as eluent to afford thealcohol intermediate (5.8 g, 95%) as a colorless oil. R_(f) 0.30(EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ 1.46 (s, 9H), 1.65-1.90 (m, 3H),2.00-2.18 (m, 3H), 2.31 (t, J=7.3 Hz, 2H), 2.30-2.50 (m, 1H), 3.35-3.75(m, 3H), 3.66 (s, 3H), 4.05-4.15 (m, 1H), 5.35-5.52 (m, 2H).

Intermediate 12.5

A DCM solution of oxalyl chloride (1.0 mL, 2.0 M, 2.0 mmol) was dilutedwith dry DCM (15 mL) and cooled to −70° C. then a solution of DMSO (0.17mL, 2.44 mmol) in DCM (7 mL) was added dropwise. After 15 min. to tinssolution was added dropwise a solution of intermediate 12.4 (0.5 g, 1.53mmol) in DCM (7 mL). The resulting solution was stirred at −70° C. for45 min. then Et₃N (1.06 mL, 7.6 mmol) was added dropwise and thesolution warmed to RT. After 15 min. the solution was diluted with DCM(50 mL) and washed with a saturated solution of NH₄Cl (2×50 mL), brine(50 mL), dried over sodium sulfate and concentrated in vacuo to affordthe aldehyde intermediate (0.49 g, 98%) used in the next step withoutfurther purification. R_(f) 0.75 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ1.48 (s, 9H), 1.50-1.75 (m, 4H), 2.00-2.15 (m, 2H), 2.28 (t, 2H),2.35-2.70 (m, 4H), 3.45-3.55 (m, 1H), 3.65 (s, 3H), 3.90-4.05 (m, 2H),5.25-5.55 (m, 2H).

A solution of the ketone intermediate (200 mg, 0.62 mmol), trimethylorthoformate (0.86 mL, 7.86 mmol), and H₂SO₄ (0.03 mL) in MeOH (3 mL)was stirred at RT for 24 h. The solution was then concentrated in vacuo,diluted with EtOAc (50 mL) and washed with saturated solution of NaHCO₃(30 mL), and brine (30 mL). The organic solution was dried andconcentrated under reduced pressure to afford the desired intermediate(160 mg, 98%) as a pale yellow oil used in the next step withoutpurification. ¹H NMR (CDCl₃) δ 1.60-1.74 (m, 2H), 1.80-2.20 (m, 6H),2.22-2.38 (m, 3H), 2.85-2.95 (m, 1H), 2.96-3.07 (m, 1H), 3.20 (s, 3H),3.26 (s, 3H), 3.67 (s, 3H), 5.35-5.55 (m, 2H); MS (m/z) 272 (M+1).

Intermediate 12.6

To a solution of intermediate 12.5 (1.50 g, 5.5 mmol) in i-PrOH (13 mL)was added a solution of D-tartaric acid (0.83 g, 5.5 mmol) in i-PrOH (12mL). The mixture was stirred at RT for 2 h then at 0° C. for 30 min. Thewhite precipitate was filtered out and washed wife small amount ofi-PrOH. The residue was diluted with EtOAc and washed with a saturatedsolution of NaHCO₃, brine, dried and concentrated in vacuo to afford thedesired chiral amine (0.38 g).

Intermediate 12.7

To a solution of intermediate 12.6 (50 mg, 0.18 mmol) in EtOH (10 mL)was added 1-phenyl-propenone (79 mg, 0.54 mmol). The resulting solutionwas stirred at reflux for 2 h, and then was concentrated in vacuo. Thecrude residue was subjected to flash chromatography and was eluted withEtOAc/hexane to afford the desired intermediate (70 mg, 93%) ascolorless oil. R_(f) 0.35 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ 1.60-1.73(m, 2H), 1.80-2.70 (m, 16H), 3.10 (s, 3H), 3.19 (s, 3H), 3.65 (s, 3H),3.60-3.80 (m, 1H), 5.30-5.50 (m, 2H), 7.10-7.40 (m, 5H); MS (m/z) 418(M+1).

Intermediate 12.8

To a mixture of intermediate 12.7 (70 mg, 0.17 mmol) in MeOH (4 mL) andwater (5 mL) were added CeCl₃ (42 mg, 0.17 mmol) followed by NaBH₄ (13mg, 0.34 mmol). After 1 h the reaction was diluted with EtAOc (20 mL)and washed with a saturated solution of NaHCO₃ (20 mL), brine (20 mL),dried and concentrated in vacuo to afford a mixture of the 2diastereoisomers intermediate (60 mg, 85%) used in the next step withoutfurther purification. R_(f) 0.20 and 0.15 (EtOAc/hexane 1/1); MS (m/z)420 (M+1).

The title compound,7-[1-(3-Hydroxy-4-phenyl-butyl)-3-oxo-pyrrolidin-2-yl]-hept-5-enoicacid, was then prepared as follows. A solution of intermediate 12.11 (50mg) in ACN (3 mL) and HCl 6M (3 mL) was stirred at RT for 4 h. Thesolution was then concentrated under reduced pressure and purified byRP-HPLC (ACN/H₂O/0.1% TFA) to afford the desired compound (30 mg) as acolorless oil ¹H NMR (CD3OD) δ 1.55-1.75 (m, 2H), 1.80-2.00 (m, 2H),2.02-2.20 (m, 2H), 2.25-2.40 (m, 2H), 2.60-2.95 (m, 6H), 3.30-3.50 (m,2H), 3.60-3.85 (m, 2H), 3.90-4.15 (m, 2H), 5.35-5.45 (m, 1H), 5.60-5.70(m, 1H), 7.15-7.40 (m, 5H); MS (m/z) 360 (M+1).

Example 13 Synthesis of(5Z)-7-{(2S)-1-[3-hydroxy-4-(3-methylphenyl)butyl]-3-oxopyrrolidin-2-yl}hept-5-enoicacid (Scheme 4, Steps A-H)

Intermediate 13.1

To a solution of intermediate 12.6 (100 mg, 0.37 mmol) in EtOH (10 mL)was added 1-(3-methylphenyl)prop-2-en-1-one (300 mg, 2.05 mmol). Theresulting solution was stirred at reflux for 2 h, and then wasconcentrated in vacuo. The crude residue was subjected to flashchromatography and was eluted with EtOAc/hexane to afford the desiredintermediate (100 mg, 63%) as colorless oil. R_(f) 0.20 (EtOAc/hexane1/1); MS (m/z) 432 (M+1).

Intermediate 13.2

To a mixture of intermediate 13.1 (100 mg, 0.23 mmol) in MeOH (5 mL) andwater (5 mL) were added CeCl₃ (90 mg, 0.37 mmol) followed by NaBH₄ (50mg, 1.34 mmol). After 1 h the reaction was diluted with EtAOc (20 mL)and washed with a saturated solution of NaHCO₃ (20 mL), brine (20 mL),dried and concentrated in vacuo to afford a mixture of the 2diastereoisomers intermediate that was separated by flash columnchromatography (EtOAc/hexane). First isomer (50 mg, 50%) R_(f) 0.40(EtOAc/hexane 4/1); MS (m/z) 434 (M+1). Second isomer (45 mg, 45%),R_(f) 0.35 (EtOAc/hexane 4/1); MS (m/z) 434 (M+1).

The title compound,(5Z)-7-{(2S)-1-[3-hydroxy-4-(3-methylphenyl)butyl]-3-3-oxopyrrolidin-2-yl}hept-5-enoicacid, was then prepared as follows. A solution of intermediate 13.2,second isomer, (45 mg, 0.10 mmol) in ACN (2 mL) and HCl 6M (3 mL) wasstirred at RT for 14 h. The solution was then concentrated under reducedpressure and purified by RP-HPLC (ACN/H₂O/0.1% TEA) to afford thedesired compound (38 mg) as colorless oil. ¹H NMR (CD3OD) δ 1.50-1.73(m, 2H), 1.75-1.97 (m, 2H), 2.03-2.18 (m, 2H), 2.3 (s, 3H), 2.55-2.90(m, 6H), 3.20-3.55 (m, 2H), 3.60-3.82 (m, 2H), 3.87-4.15 (m, 2H),5.35-5.48 (m, 1H), 5.58-5.72 (m, 1H), 6.95-7.20 (m, 4H); MS (m/z) 374(M+1).

Example 14 Synthesis of7-[3-Chloro-1-(3-hydroxy-4-m-tolyl-butyl)-pyrrolidin-2-yl]-hept-5-enoicacid (Scheme 4, Steps A-D and I-N)

Intermediate 14.1

To a solution of intermediate 12.4 (0.5 g, 1.53 mmol) in pyridine (5 mL)was added tosyl chloride. The solution was stirred at RT for 10 h thenat 50° C. for an additional 4 h. The reaction mixture was concentratedin vacuo, diluted with EtOAc (100 mL) and washed with HCl 1.0 M (100mL), brine (100 mL), dried over sodium sulfate and concentrated invacuo. The crude residue was purified by silica gel flash columnchromatography using EtOAc/hexane as eluant to afford the desiredintermediate (0.51 g, 70%) as colorless oil. R_(f) 0.3 (EtOAc/hexane1/4); ¹H NMR (CDCl₃) δ 1.20-1.30 (m, 1H), 1.41 (s, 9H), 1.60-1.75 (m,2H), 1.90-2.15 (m, 4H), 2.20-2.50 (m, 3H), 2.45 (s, 3H), 3.20-3.45 (m,2H), 3.64 (s, 3H), 3.85-3.95 (m, 1H), 4.91 (q, J=6.6 Hz, 1H), 5.30-5.45(m, 2H), 7.32 (d, J=8.1 Hz, 2H)), 7.78 (d, J=8.1 Hz, 2H).

Intermediate 14.2

To a solution of intermediate 14.1 (0.9 g, 1.80 mmol) in dry toluene (60mL) was added tetrabutyl ammonium chloride (5.0 g, 18.0 mmol). Thereaction mixture was stirred at 55° C. for 48 h then was diluted withwater and extracted with EtOAc (2×100 mL). The collected organic phasewas washed with water (2×100 mL), saturate solution of NaHCO₃ (100 mL),and brine (100 mL). The organic solution was dried over sodium sulfateand concentrated in vacuo to afford the chloride intermediate (0.6 g,96%) as a colorless oil. R_(f) 0.50 (EtOAc/hexane 1/4); ¹H NMR (CDCl₃) δ1.46 (s, 9H), 1.60-1.75 (m, 2H), 2.02-2.16 (m, 4H), 2.25-2.55 (m, 4H),3.38-3.70 (m, 2H), 3.66 (s, 3H), 3.87-4.08 (m, 1H), 4.15-4.25 (m, 1H),5.30-5.55 (m, 2H).

The previous intermediate (0.30 g, 0.87 mmol) was treated with a 4Msolution of HCl in dioxane (6 mL). The resulting solution was stirred at0° C. for 2 h then was concentrated under reduced pressure. The cruderesidue was diluted with a saturated solution of NaHCO₃ (50 mL) andextracted with EtOAc (3×40 mL). The collected organic phase was washedwith brine (100 mL), dried over sodium sulfate and concentrated underreduced pressure to afford the amine intermediate (0.24 g, 95%) used inthe next step without further purification. MS (m/z): 246 (M+1).

Intermediate 14.3

To a solution of intermediate 14.2 (100 mg, 0.41 mmol) in EtOH (10 mL)was added 1-m-tolyl-propenone (326 mg, 2.04 mmol). The resultingsolution was stirred at reflux for 2 h, and then was concentrated invacuo. The crude residue was subjected to flash chromatography and waseluted with EtOAc/hexane to afford the desired intermediate (150 mg,95%) as colorless oil. R_(f) 0.80 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ1.62-1.73 (m, 2H), 1.80-2.70 (m, 13H), 2.90-3.00 (m, 1H), 3.05-3.15 (m,1H), 3.19 (s, 3H), 3.65 (s, 3H), 3.72 (s, 2H), 3.87-3.97 (m, 1H),5.35-5.50 (m, 2H), 7.00-7.25 (4H); MS (m/z) 406 (M+1).

Intermediate 14.4 and 14.5

To a mixture of intermediate 14.3 (150 mg, 0.37 mmol) in EtOH (5 mL) andwater (5 mL) were added CeCl₃ (91 mg, 0.37 mmol) followed by NaBH₄ (42mg, 1.11 mmol). After 1 h the reaction was diluted with EtAOc (20 mL)and washed with a saturated solution of NaHCO₃ (20 mL), brine (20 mL),dried and concentrated in vacuo to afford a mixture of the 2diastereoisomers intermediate that were separated by flash columnchromatography on silica gel (EtOAc/hexane). Intermediate 3.4 (50 mg):R_(f) 0.40 (EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ 1.60-1.75 (m, 2H),1.90-2.50 (m, 17H), 2.75-2.85 (m, 2H), 2.95-3.05 (m, 1H), 3.30-3.40 (m,1H), 33.65 (s, 3H), 3.90-4.04 (m, 2H), 5.35-5.55 (m, 2H), 6.95-7.25 (m,4H); MS (m/z) 408 (M+1). Intermediate 3.5 (54 mg): R_(f) 0.35(EtOAc/hexane 1/1); ¹H NMR (CDCl₃) δ 1.45-1.80 (m, 4H), 1.95-2.50 (m,13H), 2.55-2.90 (m, 4H), 3.05-3.20 (m, 2H), 3.60 (s, 3H), 3.90-4.10 (m,2H), 5.40-5.55 (m, 2H), 6.95-7.22 (m, 4H); MS (m/z) 408 (M+1).

The title compound,7-[3-Chloro-1-(3-hydroxy-4-m-tolyl-butyl)-pyrrolidin-2-yl]-hept-5-enoicacid (first isomer in TLC), then was prepared as follows. To a solutionof intermediate 14.4 (50 mg, 0.12 mmol) in water (0.4 mL), MeOH (1.2mL), and THF (1.2 mL) was added NaOH (32 mg, 0.8 mmol). The resultingsolution was stirred at RT for 5 h then concentrated under reducedpressure. The crude mixture was purified by RP-HPLC using ACN/H₂O/0.1%TFA to afford the desired compound (25 mg). ¹H NMR (CD₃OD) δ 1.62-1.95(m, 4H), 2.10-2.20 (m, 2H), 2.25-2.40 (m, 5H), 2.50-2.70 (m, 3H),2.70-2.90 (m, 2H), 3.25-3.40 (m, 2H), 3.45-3.65 (m, 2H), 3.70-3.88 (m,2H), 3.91-4.03 (m, 1H), 4.38-4.49 (m, 1H), 5.40-5.50 (m, 1H), 5.65-5.79(m, 1H), 6.98-7.22 (m, 4H); MS (m/z) 394 (M+1).

Example 15a and 15b (5Z)-7-{(trans-2,3)-3-Chloro-1-[(4S and 4R)-hydroxy-4-(1-butylcyclobutyl)butyl]pyrrolidin-2-yl}hept-5-enoic acid(Scheme 2, Steps A-F)

Intermediate 15.1: 1-Butylcyclobutanecarboxylic acid.A solution of lithium di-isopropylamide (100 mL, 2.0 M, 200 mmol) inheptane/tetrahydrofuran/benzene was diluted with 100 mL of anhydrousTHF. To the LDA solution at 0° C. was added dropwise 10 g (100 mmol) ofcyclobutanecarboxylic acid in 15 mL of anhydrous THF over 20 minutesunder Argon. The mixture was stirred at room temperature for 3 hours. Tothe reaction mixture was added 11.4 mL (100 mmol) of butyl iodide at 0°C. The reaction mixture was warmed to RT and stirred overnight. HCl (2N)was used to adjust the pH to 2˜3. The mixture was extracted with EtOAc(3×200 mL). The combined organic phase was washed with 100 mL of brine,dried (MgSO₄) and concentrated. Thus obtained crude product was useddirectly for next step.

Intermediate 15.2: (1-Butylcyclobutyl)methanol.

To a solution of lithium aluminum hydride (120 mL, 1.0 M, 150 mmol) inTHF was added dropwise at RT a solution of intermediate 15.1 synthesizedabove in THF (25 mL). The mixture was heated at reflux for 30 minutes,and allowed to cool to it overnight Water was added dropwise at 0° C.until no bubbles corning off. The mixture was filtered through a Celitepad, washed with ether (3×150 mL). The filtrate was concentrated. Flashchromatography of the crude product over silica gel, eluting withEtOAc/hexanes (1:10) afforded 8.83 g (62% 2 steps) of the pure productas a colorless oil. R_(f) 0.5 (EtOAc/hexanes 1:4). ¹HNMR (CDCl₃) δ 3.53(s, 2H), 1.65˜1.90 (m, 4H), 1.40˜1.55 (m, 2H), 1.15˜1.35 (m, 4H), 0.95(t, J=7.3 Hz, 3H).Intermediate 15.3: 1-butylcyclobutanecarbaldehydeTo 31.6 mL of 2.0 M (63.3 mmol) of oxalyl chloride in dichloromethanewas added 100 mL of DCM followed by 9.0 mL (126 mmol) ofdimethylsulfoxide under Ar at −78° C. The mixture was stirred at −78° C.for 30 min. To this mixture was added 6.00 g (42.2 mmol) of(1-butylcyclobutyl)methanol in 10 mL of DCM. The temperature was allowedto warm to −40° C. over 40 minutes. To this mixture was added 35.3 mL(253 mmol) of Et₃N dropwise. After the addition was completed, thetemperature was allowed to warm to 0° C. over 1 hr. Water (30 mL) wasadded to the reaction mixture. The pH of the mixture was adjusted to ˜6using 2N HCl. After extraction with DCM (2×100 mL), the combined organicphase was combined, washed with brine, dried (Na₂SO₄). Concentrationafforded 6.0 g of the crude product as colorless oil, which was useddirectly for next step.Intermediate 15.4: 1-(1-Butylcyclobutyl)prop-2-yn-1-olTo 253 mL of 0.5 M (126 mmol) of ethynylmagnesium bromide solution inTHF was added 5.92 g (42.2 mmol) of crudel-butylcyclobutanecarbaldehydesynthesized above in 10 mL of THF at −60° C. The reaction mixture wasallowed to warm to 0° C. over 1.5 hr. The mixture was cooled again to−60° C., 50 mL of saturated aqueous NH₄Cl was added dropwise to quenchthe reaction. After warmed to rt, the mixture was extracted with EtOAc(3×100 mL). The combined organic phase was washed with 50 mL of brine,dried (MgSO₄), concentrated. The crude product (6.26 g) was obtained ascolorless oil, which was used directly in the next step.Intermediate 15.5:tert-Butyl(dimethyl){[1-(1-butylcyclobutyl)prop-2-ylnyl]oxy}silaneTo 6.26 g (37.6 mmol) of crude 1-(1-butylcyclobutyl)prop-2-yn-1-ol inDMF (20 mL) were added imidazole (3.1 g, 45.2 mmol) andtert-butyldimethylsilyl chloride (6.8 g, 45.2 mmol). The reactionmixture was stirred at RT overnight, then concentrated to remove DMF,diluted with 100 ml of EtOAc, and added 100 mL of sat aq. NH₄Cl. Afterseparation, the aq. phase was extracted with EtOAc (2×100 mL). Thecombined organic phase was washed with 50 mL of brine, dried (Na₂SO₄),concentrated. Flash chromatography over silica gel of the crude product(eluted with hexanes) afforded the title intermediate (6.82 g, 58% 3steps) as colorless oil.Intermediate 15.6:4-{[tert-Butyl(dimethyl)silyl]oxy}-4-(1-butylcyclobutyl)but-2-yn-1-olTo a solution of intermediate 15.5 (6.82 g, 24.3 mmol) in THF (150 mL)was added dropwise at −78° C. a solution of n-BuLi in hexanes (18.2 mL,1.6 M, 29.2 mmol). The mixture was stirred at the same temperature for40 min, after which of paraformaldehyde (1.82 g, 60.8 mmol) was added inone portion under. After stirring at −78° C. for 10 min., the bath wasremoved, and the mixture was allowed to warm to RT overnight. Sat. aq.NH₄Cl (100 mL) was added, followed by 200 mL of EtOAc. The organic phasewas separated and the aq. phase was extracted with 2×100 mL of EtOAc.The combined organic phase was washed with 100 mL of brine, dried(Na₂SO₄), and concentrated under vacuum. Chromatography (silica gel,1:15 EtOAc/hexanes) of the crude product afforded the title intermediate(4.15 g, 55%) as colorless oil. R_(f) 0.3 (1:15 EtOAc/hexanes). ¹HNMR(CDCl₃) δ 4.29 (s, 2H), 4.24 (s, 1H), 1.95˜2.10 (m, 2H), 1.74˜1.82 (m,2H), 1.40˜1.70 (m, 4H), 1.20˜1.35 (m, 4H), 0.93 (s, 3H), 0.90 (s, 9H),0.14 (s, 3H), 0.09 (s, 3H).Intermediate 15.7:4-{[tert-Butyl(dimethyl)silyl]oxy}-4-(1-butylcyclobutyl)butan-1-olTo a solution of Intermediate 15.6 (2.00 g, 6.44 mmol) in MeOH (100 mL)was added of 10% Pd/C (340 mg, 0.32 mmol). The mixture was subjected toParr hydrogenation for 2 hr. The reaction mixture was filtered through acelite pad, washed with MeOH, and concentrated in vacuo. The crudeproduct (1.91 g) was used in the next step without further purification.Intermediate 15.8:4-{[tert-Butyl(dimethyl)silyl]oxy}-4-(1-butylcyclobutyl)butanalde-hydeA solution of oxalyl chloride in dichloromethane (4.6 mL, 2.0 M, 9.2mmol) cooled at −78° C. was diluted with DCM (12 mL) then a solution ofDMSO (1.30 mL, 18.4 mmol) in DCM (5 mL) was added dropwise. The solutionwas stirred at −78° C. for 30 mm then a solution of intermediate 15.7(1.91 g, 6.07 mmol) in DCM (2 mL) was added dropwise. The temperaturewas allowed to warm to −40° C. over 30 minutes. To this mixture wasadded dropwise Et₃N (5.1 mL, 36.4 mmol). After the addition wascompleted, the temperature was allowed to warm to 0° C. over 1 hr. ThepH of the mixture was adjusted to ˜6 using 2N HCl. After extraction withDCM (3×50 mL), the combined organic phase was combined, washed withbrine, dried (Na₂SO₄). Concentration afforded of the crude product,which was subjected to chromatography (silica gel, 1:15 EtOAc/Hexanes).The desired product oil (0.96 g, 48%, 2 steps) was obtained as colorlessoil. ¹HNMR (CDCl₃) δ 9.77 (s, 1H), 3.50˜3.55 (m, 1H), 2.40˜2.50 (m, 1H),2.08˜2.16 (m, 2H), 1.15˜1.95 (m, 15H), 0.93 (s, 3H), 0.90 (s, 9H), 0.05(s, 6H).Intermediate 15.9:Methyl(5Z)-7-{(trans-2,3)-1-[4-{[tert-butyl(dimethyl)silyl]oxy}-4-(1-butylcyclobutyl)butyl]-3-chloropyrrolidin-2-yl}hept-5-enoateTo a mixture of intermediate 1.9 (100 mg, 0.407 mmol) and intermediate15.8 (128 mg, 0.407 mmol) in anhydrous MeOH (5 mL) was added dropwise asolution of NaCNBH₃ in THF (0.82 mL, 1.0 M) in THF. After 4 hrs at RT,the reaction mixture was concentrated, and diluted with 15 mL of EtOAc,washed with 10 mL of sat. aq. solution NaHCO₃. The aq. phase wasextracted with 2×10 mL of EtOAc. Combined organic phase was washed with10 mL of brine, dried (Na₂SO₄), concentrated. Flash chromatography oversilica gel (eluted with 1:15 EtOAc/Hexanes) afforded 30 mg (14%) of themixed distereomeric products as a colorless oil. R_(f) 0.37 (1:9EtOAc/hexanes). MS (m/z) 542.5 (M+1).Intermediate 15.10 and Intermediate 12.11:Methyl(5Z)-7-{(trans-2,3)-3chloro-1-[(4S and4R)-4-hydroxy-4-(1-butylcyclobutyl)butyl]pyrrolidin-2-yl}hept-5-enoate(1stisomer)To the distereomeric mixtures of intermediate 15.9 (30 mg, 0.06 mmol)was added 2.5 mL of 4.0 M of HCl in dioxane. The reaction mixture wasstirred at RT for 2 hr. It was then concentrated, diluted with EtOAc (5mL), washed with 5 mL of sat aq. NaHCO₃. The aq. phase was extractedwith 3×5 mL of EtOAc. The combined organic phase was washed with 5 mL ofbrine, dried (Na₂SO₄), concentrated. After chromatography, the 1stdiastereoisomer (Intermediate 15.10: 4 mg, 16%) 4 mg, 16%)) and 4 mg ofthe second diastereoisomer (Intermediate 15.11: 4 mg, 16%) were isolatedboth as colorless oil.Intermediate 15.10: 1 HNMR (CDCl₃) δ 5.40˜5.55 (m, 2H), 3.67 (s, 3H),3.45 (broad, 1H), 3.25 (broad, 1H), 2.35˜2.30 (m, 2H), 2.25˜1.50 (m,21H), 1.20˜1.45 (m, 8H), 0.90˜0.95 (m, 3H). MS (m/z) 428.3.Intermediate 12.11 ¹HNMR (CDCl₃) δ 5.40˜5.55 (m, 2H), 3.67 (s, 3H), 3.45(broad, 1H), 3.25 (broad, 1H), 2.35˜2.30 (m, 2H), 2.25˜1.50 (m, 21H),1.20˜1.45 (m, 8H), 0.90˜0.95 (m, 3H). MS (m/z) 428.3.

Example 15a(5Z)-7-{(trans-2,3)-3-Chloro-1-[4-hydroxy-4-(1-butylcyclobutyl)butyl]-pyrrolidin-2-yl}hept-5-enoicacid (1st isomer)

To 4.0 mg (4.3 μmol) of Intermediate 15.10 was added 0.5 mL of 1.0 NNaOH in MeOH, 0.5 mL of THF and 4 drops of water. The mixture wasstirred at rt for 60 hr. After concentration, the mixture was extractedwith 3×7 mL of EtOAc. The combined organic phase was washed with brineand dried (Na₂SO₄). Concentration afforded the product as an organicfilm (quantitative). ¹HNMR (CD3OD) δ 5.65˜5.75 (m, 1H), 5.45˜5.55 (m,1H), 3.40˜3.80 (m, 9H), 2.10˜2.70 (m, 10H), 1.45˜2.10 (m, 13H),1.20˜1.45 (m, 4H), 0.88˜0.98 (m, 3H). MS (m/z) 414.3

Example 15b(5Z)-7-{(trans-2,3)-3-Chloro-1-[4-hydroxy-4-(1-butylcyclobutyl)-butyl]pyrrolidin-2-yl}hept-5-enoicacid (2nd isomer)

To 4.0 mg (4.3 μmol) of Intermediate 15.11 was added 0.5 mL of 1.0 NNaOH in MeOH, 0.5 mL of THF and 4 drops of water. The mixture wasstirred at rt for 60 hr. After concentration, the mixture was extractedwith 3×7 mL of EtOAc. The combined organic phase was washed with brineand dried (Na₂SO₄). Concentration afforded the product as an organicfilm (quantitative). ¹HNMR (CD₃OD) δ 5.65˜5.75 (m, 1H), 5.45˜5.55 (m,1H), 3.40˜3.80 (m, 9H), 2.10˜2.70 (m, 10H), 1.45˜2.10 (m, 13H),1.20˜1.45 (m, 4H), 0.89˜0.99 (m, 3H). MS (m/z) 414.3.

Example 16a and 16b Synthesis of (5Z)-7-{(2S,3R)-3-chloro-1-[(3R and3S)-3-hydroxy-4-(3-methylphenyl)butyl]pyrrolidin-2-yl}hept-5-enoic acid(Scheme 4, Steps A-D and I-N)

Intermediate 16.1: N-methoxy-N-methyl-2-(3-methylphenyl)acetamide.To a solution of m-tolyl acetic acid (2.0 g, 0.013 mol) in DMF (20 mL)were added N,O-dimethyl hydroxylamine hydrochloride (1.6 g, 0.016 mol),EDC (3.06 g, 0.016 mol), HOAt (2.17 g, 0.016 mol), and DiPEA (11.6 mL,0.067 mol). The resulting solution was stirred at RT for 18 h then wasdiluted with EtOAc (200 mL) and washed with HCl 1M (100 mL), water (100mL), sat sol. NaHCO₃ (100 mL), and brine (100 mL). The organic phase wasdried over sodium sulfate and concentrated in vacuo to afford the titleintermediate (2.2 g, 88%) as colorless oil used in the next step withoutfurther purification.Intermediate 16.2: 1-(3-methylphenyl)but-3-en-2-one.To a solution of intermediate 16.1 (2.2 g, 0.011 mol) in dry THF (100mL) was added dropwise at 0° C. a solution of vinyl magnesium bromide(12 mL, 1.0 M, 0.012 mol). The resulting solution was stirred at 0° C.for 1 h then was quenched with a saturated solution of NH4Cl (100 mL).The mixture was extracted with EtOAc (2×100 mL). The collected organicphase was washed with brine, dried, and concentrated under vacuum toafford the title intermediate used in the next step without furtherpurification.Intermediate 16.3: methyl(5Z)-7-{(2S,3R)-3-chloro-1-[4-(3-methylphenyl)-3-oxobutyl]pyrrolidin-2-yl}hept-5-enoate.A mixture of intermediate 1.9 (100 mg, 0.407 mmol) and intermediate 16.2(326 mg, 2.0 mmol) in EtOH (5 mL) was refluxed 2 h then concentratedunder reduced pressure. The crude residue was purified by silica gelcolumn chromatography (EtOAc/hexanes) to afford the title compound (150mg, 95%) as colorless oil. R_(f) 0.8 (EtOAc/hexanes 1/1);Intermediate 16.4 and 16.5: methyl (5Z)-7-{(2S,3R)-3-chloro-1-[(3S, and3R)-3-hydroxy-4-(3-methylphenyl)butyl]pyrrolidin-2-yl}hept-5-enoate.To a mixture of intermediate 16.3 (150 mg, 0.37 mmol) in EtOH (5 mL) andwater (5 mL) were added CeCl₃.H₂O (91 mg, 0.37 mmol) followed by NaBH₄(42 mg, 1.11 mmol). After 1 h the reaction was diluted with EtOAc (20mL) and washed with a saturated solution of NaHCO₃ (20 mL), brine (20mL), dried and concentrated in vacuo to afford a mixture of the 2diastereoisomers intermediate that were separated by silica gel columnchromatography (EtOAc/hexane). Intermediate 13.4 (50 mg): R_(f) 0.40(EtOAc/hexane 1/1); MS (m/z) 408 (M+1). Intermediate 13.5 (40 mg): R_(f)0.35 (EtOAc/hexane 1/1); MS (m/z) 408 (M+1).

Example 16a(5Z)-7-{(2S,3R)-3-chloro-1-[(3S)-3-hydroxy-4-(3-methylphenyl)butyl]pyrrolidin-2-yl}hept-5-enoicacid

To a solution of intermediate 16.4 (50 mg, 0.13 mmol) in THF (2 mL) andMeOH (2 mL) was added a solution of NaOH (0.98 mg) in H₂O (0.7 mL). Theresulting solution was stirred at RT for 4 hours. The solution was thenpurified by RP-HPLC (ACN/H2O 0.1% TFA) to afford the desired compound(22 mg).

Example 16b(5Z)-7-{(2S,3R)-3-chloro-1-[(3R)-3-hydroxy-4-(3-methylphenyl)butyl]pyrrolidin-2-yl}hept-5-enoicacid

To a solution of intermediate 16.5 (50 mg, 0.13 mmol) in THF (2 mL) andMeOH (2 mL) was added a solution of NaOH (0.98 mg) in H₂O (0.7 mL). Theresulting solution was stirred at RT for 4 hours. The solution was thenpurified by RP-HPLC (ACN/H2O 0.1% TFA) to afford the desired compound(32 mg).

Example 174-{2-[(2S,3R)-3-chloro-1-(4-hydroxynonyl)pyrrolidin-2-yl]ethyl}-benzoicacid (Scheme 3 Steps A-C and G-L)

Intermediate 17.1: methyl4-{2-[(2S,3R)-1-((4R)-4-{[tert-butyl(dimethyl)silyl]oxy}nonyl)-3-chloropyrrolidin-2-yl]ethyl}benzoate.To a solution of intermediate 8.3 (0.15 g, 0.56 mmol) and intermediate1.13 (0.23 g, 0.84 mmol) in MeOH (10 mL) was added a solution of NaCNBH₃in THF (1.0 mL, 1.0M, 1.20 mmol). The resulting solution was stirred atRT for 18 h then was concentrated in vacuo, diluted with EtOAc (50 mL)and washed with a saturated solution of NaHCO₃ (50 mL), and brine (50mL). The organic solution was dried over sodium sulfate and concentratedin vacuo. The crude residue was purified by silica gel flash columnchromatography (EtOAc/hexanes) to afford the desired intermediate (0.08g, 30%) as a colorless oil. R_(f) 0.70 (EtOAc/hexane 3/7); MS (m/z): 524(M+1).Intermediates 17.2:methyl-4-(2-{(2S,3R)-3-chloro-1-[(4R)-4-hydroxynonyl]pyrrolidin-2-yl}ethyl)benzoateTo a solution of intermediate 17.1 (0.08 g) in dioxane (2 mL) was addeda solution of HCl in dioxane (2 mL, 4.0 M). The solution was stared atRT for 2 h then was concentrated under reduced pressure. The cruderesidue was diluted with a saturated solution of NaHCO₃ (20 mL) andextracted with EtOAc (3×30 mL). The collected organic phase was washedwith brine, dried, and concentrated under reduced pressure to afford thetitle intermediate that was used in the next step without furtherpurification. MS (m/z): 450.3 (M+1).

Example 174-{2-[(2S,3R)-3-chloro-1-(4-hydroxynonyl)pyrrolidin-2-yl]ethyl}benzoicacid

To a solution of intermediate 17.2 in MeOH (2 mL) and THF (2 mL) wasadded a solution of NaOH (0.09 g) in water (0.7 mL). The resultingsolution was stirred at RT for 4 h, and then was purified by RP-HPLC(ACN/H₂O 0.1% TFA) to afford the title compound (38 mg). MS (m/z) 374(M+1).

Example 18 Synthesis of(5Z)-7-{1-[3-hydroxy-3-(1-phenylcyclopropyl)propyl]-3-oxopyrrolidin-2-yl}hept-5-enoicacid (Scheme 1, Steps A-H)

Intermediate 16.1: N-methoxy-N-methyl-1-phenylcyclopropanecarboxamide.The title compound was prepared according to the procedure described forintermediate 16.1 from 1-phenyl-1cyclopropane carboxylic acid. R_(f)0.30 (EtOAc/hexanes 3/7).Intermediate 18.2: 1-(1-phenylcyclopropyl)prop-2-en-1-one.The title compound was prepared according to the procedure described forintermediate 16.2 using intermediate 16.1. R_(f) 0.90 (EtOAc/hexanes3/7).Intermediate 18.3:methyl(5Z)-7-{(2S)-3,3-dimethoxy-1-[3-oxo-3-(1-phenylcyclopropyl)propyl]pyrrolidin-2-yl}hept-5-enoate.The title compound was prepared according to the procedure described forintermediate 13.1 frommethyl(5Z)-7-[(2S)-3,3-dimethoxypyrrolidin-2-yl]hept-5-enoate(intermediate 5.3) and intermediate 18.2. R_(f) 0.30 (EtOAc/hexanes1/1); MS (m/z) 444 (M+1).Intermediate 18.4:methyl(5Z)-7-{1-[3-hydroxy-3-(1-phenylcyclopropyl)propyl]-3,3-dimethoxypyrrolidin-2-yl}hept-5-enoate.The title compound was prepared according to the procedure described forintermediate 13.2 from intermediate 18.3. (mixture of diastereoisomers)R_(f) 0.50 & 0.45 (EtOAc/hexanes 1/1); MS (m/z) 446 (M+1).

Example 18(5Z)-7-{1-[3-hydroxy-3-(1-phenylcyclopropyl)propyl]-3-oxopyrrolidin-2-yl}hept-5-enoicacid

The title compound was prepared as TFA salt according to the proceduredescribed in Example 13 from Intermediate 18.4. MS (m/z) 386 (M+1).

Example 19 Synthesis of7-(1-{4-[1-(cyclopropylmethyl)cyclopropyl]-4-hydroxybutyl}-3-oxopyrrolidin-2-yl)heptanoicacid (Scheme 1, Steps A-F and I, L, N, O)

Intermediate 19.1: 1-(cyclopropylmethyl)cyclobutanecarboxylic acid.The title compound was prepared according to the procedure described forIntermediate 15.1 from cyclobutanecarboxylic acid and(bromomethyl)cyclopropane.Intermediate 19.2: [1-(cyclopropylmethyl)cyclobutyl]methanol.The title compound was prepared according to the procedure described forIntermediate 15.2 from intermediate 19.1.Intermediate 19.3: 1-(cyclopropylmethyl)cyclobutanecarbaldehyde.The title compound was prepared according to the procedure described forIntermediate 15.3 from intermediate 19.2.Intermediate 19.4: 1-[1-(cyclopropylmethyl)cyclobutyl]prop-2-yn-1-ol.The title compound was prepared according to the procedure described forIntermediate 15.4 from intermediate 19.3.Intermediate 19.5:tert-butyl({1-[1-(cyclopropylmethyl)cyclobutyl]prop-2-ynyl}oxy)dimethylsilane.The title compound was prepared according to the procedure described forIntermediate 15.5 from intermediate 19.4. R_(f) 0.8 (EtOAc/hexanes 1/9).Intermediate 19.6:4-{[tert-butyl(dimethyl)silyl]oxy}-4-[1-(cyclopropylmethyl)cyclobutyl]but-2-yn-1-ol.The title compound was prepared according to the procedure described forIntermediate 15.6 from intermediate 19.5. R_(f) 0.7 (EtOAc/hexanes 1/4).Intermediate 19.7:4-{[tert-butyl(dimethyl)silyl]oxy}-4-[1-(cyclopropylmethyl)cyclobutyl]butan-1-ol.The title compound was prepared according to the procedure described forIntermediate 15.7 from intermediate 19.6.Intermediate 19.8:{4-bromo-1-[1-(cyclopropylmethyl)cyclobutyl]butoxy}(tert-butyl)dimethylsilane.The title compound was prepared according to the procedure described forIntermediate 15.8 from intermediate 19.7. R_(f) 0.5 (EtOAc/hexanes 1/9).Intermediate 19.9: methyl(5Z)-7-(1-{4-{[tert-butyl(dimethyl)silyl]oxy}-4-[1-(cyclopropylmethyl)cyclopropyl]butyl}-3,3-dimethoxypyrrolidin-2-yl)hept-5-enoate.The title compound was prepared according to the procedure described forIntermediate 15.9 from intermediate 19.7 and methyl(5Z)-7-[(2S)-3,3-dimethoxypyrrolidin-2-yl]hept-5-enoate (intermediate5.3). R_(f) 0.7 (EtOAc/hexanes 3/7).Intermediate 19.10: methyl(5Z)-7-(1-{4-[1-(cyclopropylmethyl)cyclopropyl]-4-hydroxybutyl}-3-oxopyrrolidin-2-yl)hept-5-enoate.To a solution of intermediate 19.9 (0.62 g) in THF (5 mL) and H₂O (1 mL)was added a solution of HCl in dioxane (6 mL, 4.0 M). The resultingsolution was stirred at RT for 1 h, then was dilute with EtOAc (50 mL)and washed with a saturated solution of NaHCO₃ (50 mL) and brine (50mL). The organic phase was dried over sodium sulfate and concentrated invacuo to afford the title intermediate (0.15 g, 34%) used in the nextstep without further purification. R_(f) 0.4 (EtOAc/hexanes 3/2); MS(m/z) 406 (M+1).

Example 19(5Z)-7-(1-{4-[1-(cyclopropylmethyl)cyclopropyl]-4-hydroxybutyl}-3-oxopyrrolidin-2-yl)hept-5-enoicacid

To a solution of intermediate 19.10 (20 mg) in THF (0.4 mL) and MeOH(0.4 mL) was added a solution of NaOH (20 mg) in H₂O (0.13 mL). Theresulting solution was stirred at RT for 18 h then concentrated in vacuoto afford the title compound as sodium salt. MS (m/z) 392 (M+1).

Example 20 Synthesis of(5Z)-7-[(2S,3R)-3-chloro-1-(4-hydroxynonyl)pyrrolidin-2-yl]hept-5-enoicacid (Scheme 2, Steps A-B and D-F)

The title compound was prepared according to the procedure described forExample 1 from (S)-1-octyn-3-ol and rac.Methyl(5Z)-7-[(2R,3R)-3-chloropyrrolidin-2-yl]hept-5-enoate(intermediate 1.9). MS (m/z) 375 (M+1).

Example 21 Synthesis of(5Z)-7-{(2S,3R)-3-chloro-1-[4-(1-ethylcyclobutyl)-4-hydroxybutyl]pyrrolidin-2-yl}hept-5-enoicacid (Scheme 2, Steps A-B and D-F)

Intermediate 21.1: 1-ethylcyclobutanecarboxylic acidThe title compound was prepared according to the procedure described forintermediate 2.1 from cyclobutanecarboxylic acid and ethylbromide.Intermediate 21.2: (1-ethylcyclobutyl)methanol.The title compound was prepared according to the procedure described forintermediate 2.2 from 1-ethylcyclobutanecarboxylic acid (intermediate21.1). R_(f) 0.40 (EtOAc/hexanes 1/4)Intermediate 21.3: tert-butyl{[1-(1-ethylcyclobutyl)prop-2-ynyl]oxy}dimethylsilane.The title compound was prepared according to the procedure described forintermediate 2.3 from (1-ethylcyclobutyl)methanol. (intermediate 21.2).Intermediate 21.4:4-{[tert-butyl(dimethyl)silyl]oxy}-4-(1-ethylcyclobutyl)but-2-yn-1-ol.The title compound was prepared according to the procedure described forintermediate 2.4 from 1-ethylcyclobutanecarbaldehyde (intermediate21.3). R_(f) 0.50 (EtOAc/hexanes 1/5).Intermediate 21.5:4-{[tert-butyl(dimethyl)silyl]oxy}-4-(1-ethylcyclobutyl)butan-1-ol.The title compound was prepared according to the procedure described forintermediate 2.5 from 1-(1-ethylcyclobutyl)prop-2-yn-1-ol (intermediate21.4). R_(f) 0.8 (EtOAc/hexanes 1/9).Intermediate 21.6:4-{[tert-butyl(dimethyl)silyl]oxy}-4-(1-ethylcyclobutyl)butanalThe title compound was prepared according to the procedure described forintermediate 2.6 fromtert-butyl{[1-(1-ethylcyclobutyl)prop-2-ynyl]oxy}dimethylsilane.(intermediate 21.5). R_(f) 0.6 (EtOAc/hexanes 1/4).Intermediate 21.7:methyl(5Z)-7-{(2S,3R)-1-[4-{[tert-butyl(dimethyl)silyl]oxy}-4-(1-ethylcyclobutyl)butyl]-3-chloropyrrolidin-2-yl}hept-5-enoate.The title compound was prepared according to the procedure described forintermediate 2.7 from intermediate 21.6.R_(f) 0.4 (EtOAc/hexanes 1/5).Intermediate 21.8: methyl(5Z)-7-{(2S,3R)-3-chloro-1-[4-(1-ethylcyclobutyl)-4-hydroxybutyl]pyrrolidin-2-yl}hept-5-enoate.The title compound was prepared according to the procedure described forintermediate 2.8 from intermediate 21.7. R_(f) 0.8 (EtOAc/hexanes 1/5).

Example 21(5Z)-7-{(2S,3R)-3-chloro-1-[4-(1-ethylcyclobutyl)-4-hydroxybutyl]pyrrolidin-2-yl}hept-5-enoicacid

The title compound was prepared according to the procedure described forexample 2 from intermediate 21.8. MS (m/z) 387 (M+1).

Examples 22-25 Biological Assays Example 22 Prostaglandin EP2 BindingAssay

Compounds of the invention were tested in an EP2 receptor binding assayof the following protocol. As referred to herein, the term a “standardEP2 receptor binding assay” designates the following protocol whichallows the determination of the affinity of the test compounds for theEP2 receptor

A mixture containing 20 ug of EP2 receptor membranes, 0.5 mg of wheatgerm agglutinin coated PVT-SPA beads, plus or minus a pyrrolidinecompound of the invention (25 ul per well) or 10 uM of cold PGE2 at 1%DMSO and 20 nM ³H-PGE2 in assay buffer containing 25 mM MES, 10 mMMgCl₂, 1 mM EDTA, pH 6.0 are incubated in Corning 3600 plates on a plateshaker for 2 hrs at room temperature. 3H-PGE2 binding is evaluated bycounting the plates on the top count using the ³H SPA dpm2 program. %Binding and Ki value for inhibitors are calculated based on the one sitecompetition parameter using the Graphpad prism program. Ki values areset form in the Table I which follows Example 25 below.

Example 23 ER² cAMP Assay

Compounds of the invention were tested in a total cAMP assay as follows.HEK293-EBNA cells transfected with pCEP4-hEP2 receptors were seeded in96 well opaque plate (Costar #3917) at 4×10⁴ cells per well in 100 μl ofculture medium (D-MEM/F12 supplemented with 10% FBS, 2 nM L-glutamine,and 250 μg/ml of hygromycin; all from GibcoBRL) and incubated at 37° C.After overnight incubation, the medium was removed from each well andreplaced with 45 μl of assay medium consisted of phenol red freeD-MEM/F-12, 0.1% BSA (GibcoBRL) and 0.1 mM3-isobutyl-1-methyl-xanthine(Sigma). After 15 minutes of incubation at 37° C., 16-16-dimethyl PGE-2or compounds at desired concentrations in 20 μl of assay medium wereadded to cells and further incubated at 37° C. for 1 hour. Total cAMP(intra- and extra-cellular) was measured by using a cAMP-screen ELISASystem (Tropix, #CS1000). Results (EC₅₀ (μM)) are shown in the Table Iwhich follows Example 25 below.

Example 24 EP4 Binding Assay

Compounds of the invention were tested in an EP4 receptor binding assayof the following protocol which allows the determination of the affinityof the test compounds for the EP4 receptor.

A mixture containing 20 μg of EP4 receptor membranes, 0.5 mg of wheatgerm agglutinin coated PVT-SPA beads, plus or minus a compound of theinvention (25 μl per well) or 10 μM of cold PGE2 at 1% DMSO and 20 nM³H-PGE2 in assay buffer containing 25 mM MES, 10 mM MgCl₂,1 mM EDTA, pH6.0 are incubated in Corning 3600 plates on a plate shaker for 2 hrs atroom temperature. ³H-PGE2 binding is evaluated by counting the plates onthe top count using the ³H SPA dpm2 program. % Binding and Ki value forinhibitors are calculated based on the one site competition parameterusing the Graphpad prism program. EP4 Ki values are set forth in theTable I which follows Example 25 below.

Example 25 EP4 cAMP Assay

Compounds of the invention can be tested in a total cAMP assay asfollows. HEK293-EBNA cells transfected with pCEP4-hEP4 receptors wereseeded in 96 well opaque plate (Costar #3917) at 4×10⁴ cells per well in100 μl of culture medium (D-MEM/F12 supplemented with 10% FBS, 2 nML-glutamine, and 250 μg/ml of hygromycin; all from GibcoBRL) andincubated at 37° C. After overnight incubation, the medium was removedfrom each well and replaced with 45 μl of assay medium consisted ofphenol red free D-MEM/F-12, 0.1% BSA (GibcoBRL) and 0.1mM3-isobutyl-1-methyl-xanthine (Sigma). After 15 minutes of incubationat 37° C., 16-16-dimethyl PGE-2 or compounds of the invention at desiredconcentrations in 20 μl of assay medium are added to cells and furtherincubated at 37° C. for 1 hour. Total cAMP (intra- and extra-cellular)can be measured by using a cAMP-screen ELISA System (Tropix, #CS1000).

TABLE I Compound of h-EP2 h-EP2 h-EP4 Example No. Ki (μM) EC₅₀ (μM) Ki(μM) 1 5.6 0.048 ND 11 3.5 0.25 ND 13 10 0.37 0.005 15 11.0 8.5 (n = 2)0.156

The invention has been described in detail with reference to preferredembodiments thereof. However, it will be appreciated that those skilledin the art, upon consideration of this disclosure, may makemodifications and improvements within the spirit and scope of theinvention.

1. A compound according to the following Formula IV, or apharmaceutically acceptable salt thereof:

wherein A is O, S, CR²R³; B is (CR²R³)_(n), or absent; or A and B takenin combination form an optionally substituted 1,2-vinylene group or anethynyl group; V is (CR²R³)_(m), optionally substituted divalent aryl,or optionally substituted divalent heteroaryl; L is C(O)Z; G is oxo(═O), hydroxyl, or optionally substituted alkoxy; Q is (CR²R³)_(q) whichmay include 0 or 1 carbon-carbon double or triple bonds; U is anoptionally substituted alkyl group; Z is hydroxy, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted heteroalkyl, optionally substitutedheteroalkenyl, optionally substituted heteroalkynyl, amino, NR⁴R⁵,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted carbocyclic aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, or optionallysubstituted heteroarylalkyl; n is an integer selected from 0-3; m is aninteger selected from 1-6; q is an integer selected from 0-5; R² and R³are independently selected at each occurrence from the group consistingof hydrogen, hydroxy, halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted heteroalkyl, optionally substituted heteroalkenyl, andoptionally substituted heteroalkynyl; and R⁴ and R⁵ are independentlyare independently selected at each occurrence from the group consistingof hydrogen optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted heteroaryl, optionally substituted heteroalkenyl, optionallysubstituted heteroalkynyl, optionally substituted carbocyclic aryl,optionally substituted heteroaryl, optionally substituted arylalkyl, andoptionally substituted heteroarylalkyl, or R⁴ and R⁵ taken incombination is an optionally substituted heterocycloalkyl.
 2. A compoundaccording to claim 1 wherein A is CH₂.
 3. A compound according to claim1 wherein q is 1 or
 2. 4. A compound according to claim 1 wherein m is3.
 5. A compound according to claim 1 wherein Q includes 0 double bond.6. A compound of the following Formula X, or a pharmaceuticallyacceptable salt thereof:

wherein A is selected from O and CH₂; B is CR²R³ or absent wherein R²and R³ are independently selected from H and C₁-C₆ alkyl; or A and Btaken in combination form a 1,2-vinylene group; G is oxo; L is C(O)Z; Qis (CR²R³)_(q) which may include 0 or 1 C═C double bond; U is —CR⁶R⁷—W,wherein R⁶ and R⁷ are independently selected from H and C₁-C₆ alkyl; orR⁶ and R⁷ can form a C₃-C₆ cycloalkyl with the carbon they are attachedto; V is selected from aryl and heteroaryl; or V is (CR²R³)_(m) when Aand B taken in combination form a 1,2-vinylene group or an ethynylgroup; W is selected from hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl C₁-C₆alkyl, aryl and heteroaryl; Z is hydroxy; q is an integer selected from0, 1, 2, 3, 4 and 5; m is an integer selected from 1, 2, 3, 4, 5 and 6.7. A compound according to claim 6 wherein q is selected from 1 and 2.8. A compound according to claim 6 wherein m is
 3. 9. A compound of thefollowing Formula X′, or a pharmaceutically acceptable salt thereof:

wherein A is CH₂; B is CR²R³ or absent wherein R² and R³ areindependently selected from H and C₁-C₆ alkyl; G is oxo; L is C(O)Z; Qis (CR²R³)_(q) which may include 0 or 1 C═C double bond; U is —CR⁶R⁷—W,wherein R⁶ and R⁷ form a C₃-C₆ cycloalkyl with the carbon they areattached to; V is selected from (CR²R³)_(m), aryl and heteroaryl; W isselected from hydrogen, C₃-C₆ cycloalkyl and C₁-C₆ alkylC₃-C₆cycloalkyl; Z is hydroxy; q is an integer selected from 0, 1, 2, 3and 4; m is an integer selected from 1, 2, 3, 4, 5 and
 6. 10. A compoundaccording to claim 9 wherein Q includes 0 double bond.
 11. A compoundaccording to claim 9 wherein B is CH₂.
 12. A compound according to claim9 wherein q is 1 or
 2. 13. A compound according to claim 9 wherein m is3.
 14. A compound according to claim 9 wherein V is (CR²R³)_(m).
 15. Acompound of the following Formula XI, or a pharmaceutically acceptablesalt thereof:

wherein G is oxo; L is C(O)Z; Q is (CR²R³)_(q) wherein R² and R³ areindependently selected from H and C₁-C₆ alkyl; U is —CR⁶R⁷—W, wherein R⁶and R⁷ are independently selected from H and C₁-C₆ alkyl; or R⁶ and R⁷can form a C₃-C₆ cycloalkyl with the carbon they are attached to; V isselected from aryl and heteroaryl; W is selected from hydrogen, C₁-C₆alkyl and C₃-C₆ cycloalkyl C₁-C₆ alkyl; Z is hydroxy; m is an integerselected from 1, 2 and 3; q is selected from 1 and
 2. 16. A compoundaccording to claim 15 wherein m is
 3. 17. A compound according to claim15 wherein V is phenyl.
 18. A compound of following Formula XII, or apharmaceutically acceptable salt thereof:

wherein G is oxo; L is C(O)Z; Q is (CR²R³)_(q) wherein R² and R³ areindependently selected from H and C₁-C₆ alkyl, U is —CR⁶R⁷—W, wherein R⁶and R⁷ are independently selected from H and C₁-C₆ alkyl; or R⁶ and R⁷can form a C₃-C₆ cycloalkyl with the carbon they are attached to; V is(CR²R³)_(m); W is selected from aryl and heteroaryl; Z is hydroxy, q isan integer selected from 1 and 2; m is an integer selected from 1, 2 and3.
 19. A compound according to claim 18 wherein q is
 1. 20. A compoundaccording to claim 18 wherein m is
 3. 21. A compound according to claim18 wherein W is phenyl.
 22. A compound of the following Formula XIII, ora pharmaceutically acceptable salt thereof:

wherein A is O, S, or CR²R³; B is (CR²R³) m, or absent; or A and B takenin combination form an optionally substituted 1,2-vinylene group or anethynyl group; V is (CR²R³)_(m), optionally substituted divalent aryl,or optionally substituted divalent heteroaryl; L is C(O)Z; G is oxo(═O), hydroxyl, or optionally substituted alkoxy; Q is (CR²R³)_(q) whichmay include 0 or 1 C═C double bonds; U is an optionally substitutedalkyl group; Z is hydroxy, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted heteroalkyl, optionally substituted heteroalkenyl optionallysubstituted heteroalkynyl, amino, NR⁴R⁵, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted carbocyclic aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, or optionally substitutedheteroarylalkyl; n is an integer selected from 0-3; m is an integerselected from 1-6; q is an integer selected from 0-5; and R² and R³ areindependently hydroxy, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted heteroalkyl, optionally substituted heteroalkenyl,optionally substituted heteroalkynyl; R⁴ and R⁵ are independently areindependently selected at each occurrence from the group consisting ofhydrogen optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted heteroalkyl, optionally substituted heteroalkenyl,optionally substituted heteroalkynyl, optionally substituted carbocyclicaryl, optionally substituted heteroaryl, optionally substitutedarylalkyl, and optionally substituted heteroarylalkyl, or R⁴ and R⁵taken in combination is an optionally substituted heterocycloalkyl. 23.A compound of the following Formula XIV, or a pharmaceuticallyacceptable salt thereof:

wherein q is an integer from 1-3; q′ is an integer from 2-4; G is oxo ormethoxy; Z is hydroxy, C₁₋₆ alkoxy, amino or mono C₁₋₆ alkylamino ordi-C₁₋₆ alkylamino; and U is a —(CR²R³)_(s)—W, wherein R² and R³ areindependently hydrogen, hydroxy, halogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted heteroalkyl,optionally substituted heteroalkenyl, or optionally substitutedheteroalkynyl; s is an integer from 0-6; W is hydrogen or C₃₋₇cycloalkyl.
 24. A compound of the following Formula XV, or apharmaceutically acceptable salt thereof:

wherein A is O or CH₂; B is CH₂ or absent V is divalent phenyl, divalentfuran, or divalent thiophene; q is an integer from 1-3; G is oxo ormethoxy; Z is hydroxy, C₁-C₆ alkoxy, amino or mono C₁₋₆ alkylamino or diC₁₋₆ alkylamino; and U is a —(CR²R³)_(s)—W, wherein R² and R³ areindependently hydrogen, hydroxy, halogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted alkenyl;optionally substituted alkynyl, optionally substituted heteroalkyl,optionally substituted heteroalkenyl, or optionally substitutedheteroalkynyl; s is an integer from 0-6; and W is hydrogen orC₃₋₇cycloalkyl.
 25. A compound according to claim 6 wherein the compoundis: methyl 7-[(2R)-1-(3-hydroxyoctyl)-3-oxopyrrolidin-2-yl]hept-5-enoate(5Z)-7-{1-[3-hydroxy-3-(1-phenylcyclopropyl)propyl]-3-oxopyrrolidin-2-yl}hept-5-enoicacid;(5Z)-7-{1-[3-hydroxy-4-(3-methylphenyl)butyl]-3-oxopyrrolidin-2-yl}hept-5-enoic acid;(5Z)-7-[1-(3-hydroxy-4phenylbutyl)-3-oxopyrrolidin-2-yl]hept-5-enoicacid;7-(1-{4-[1-(cyclopropylmethyl)cyclobutyl]-4-hydroxybutyl}-3-oxopyrrolidin-2-yl)heptanoicacid; or a pharmaceutically acceptable salt thereof.
 26. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and one or more compounds according to claim
 1. 27. Acomposition according to claim 26 wherein the compound is packagedtogether with instructions for use of the compound to treat pretermlabor, dysmenorrhea, asthma, hypertension, infertility or a fertilitydisorder, sexual dysfunction, undesired blood clotting, a destructivebone disease or disorder, preeclampsia or eclampsia, or an eosinophildisorder.
 28. A composition according to claim 26 wherein thecomposition further comprises one or more phosphodiesterase inhibitorcompounds.